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| BabyScreen+ newborn screening v1.98 | SGPL1 |
Zornitza Stark Tag renal was removed from gene: SGPL1. Tag treatable tag was added to gene: SGPL1. Tag endocrine tag was added to gene: SGPL1. |
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| BabyScreen+ newborn screening v1.87 | PSTPIP1 |
Zornitza Stark gene: PSTPIP1 was added gene: PSTPIP1 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: PSTPIP1. Mode of inheritance for gene: PSTPIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PSTPIP1 were set to Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416 Review for gene: PSTPIP1 was set to GREEN Added comment: Established gene-disease association. Onset in childhood. Treatment: adalimumab and tacrolimus, NSAIDs, corticosteroids, BMT non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v1.83 | POMC | Zornitza Stark Phenotypes for gene: POMC were changed from Proopiomelanocortin deficiency to Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.81 | POMC | Zornitza Stark reviewed gene: POMC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.80 | POLE |
Zornitza Stark gene: POLE was added gene: POLE was added to BabyScreen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: POLE. Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POLE were set to IMAGE-I syndrome, MIM# 618336 Review for gene: POLE was set to GREEN Added comment: Established gene-disease association. Multi-system disorder comprising GH and adrenal hypoplasia. Treatment: hydrocortisone non-genetic confirmatory testing: hormone levels Sources: Expert list |
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| BabyScreen+ newborn screening v1.70 | IRF8 |
Zornitza Stark gene: IRF8 was added gene: IRF8 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IRF8. Mode of inheritance for gene: IRF8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IRF8 were set to Immunodeficiency 32B, monocyte and dendritic cell deficiency, autosomal recessive, MIM# 226990 Review for gene: IRF8 was set to GREEN Added comment: At least 4 families reported with bi-allelic variants. Gene-disease association also proposed for mono-allelic variants but only two individuals reported. Recurrent infections presenting in infancy. Treatment: BMT Non-genetic confirmatory testing available Sources: Expert list |
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| BabyScreen+ newborn screening v1.35 | CEBPE |
Zornitza Stark gene: CEBPE was added gene: CEBPE was added to BabyScreen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: CEBPE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CEBPE were set to Specific granule deficiency, MIM# 245480 Review for gene: CEBPE was set to GREEN Added comment: Established gene-disease association. Recurrent infections in infancy and childhood. Treatment: long term antimicrobial prophalaxis Non-genetic confirmatory testing available Sources: Expert Review |
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| BabyScreen+ newborn screening v1.23 | TRAC |
Zornitza Stark gene: TRAC was added gene: TRAC was added to BabyScreen+ newborn screening. Sources: Expert Review founder, technically challenging tags were added to gene: TRAC. Mode of inheritance for gene: TRAC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAC were set to 21206088 Phenotypes for gene: TRAC were set to Immunodeficiency 7, TCR-alpha/beta deficient, MIM#615387 Review for gene: TRAC was set to RED Added comment: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2177 | DMD | Zornitza Stark edited their review of gene: DMD: Added comment: Reviewed with RCH Neurology team: treatments currently not approved by the TGA. Downgrade to Amber, can be upgraded when this changes.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2175 | COL4A6 |
Zornitza Stark edited their review of gene: COL4A6: Added comment: Further review of PMID:33840813; Family A: - Proband is hemi for COL4A6 and het for GJB2. Mother is het for COL4A6 - hypothesised that in the proband is more severe than the parents due to additive effects of his two variants however, mother's audiometric data was unavailable to confirm this. Family B: - Variant does not segregate within family with the proband being WT in this gene - NM_001287758.1: c.3272G>C is the mutation however, it appears to be an annotation error as it corresponds to NC_000023.11:g.108171443 in GRCh38. At that position, the c. is T not G and the amino acid residue is Val, not Gly. In addition, there is a missense affecting Gly of GXY in gnomad v3 with 38 hemis.; Changed rating: RED; Changed publications: 33840813; Changed phenotypes: Deafness, X-linked 6 MIM#300914; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females |
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| BabyScreen+ newborn screening v0.2158 | AMT |
Zornitza Stark edited their review of gene: AMT: Added comment: Severe infantile forms: treatment does not currently alter outcomes. Attenuated forms can have onset in childhood, therapy with sodium benzoate and NMDA (The N-methyl-D-aspartate receptor) receptor site antagonists (dextromethorphan, ketamine) but uncertainty about effectiveness.; Changed rating: AMBER; Changed publications: 35683414 |
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| BabyScreen+ newborn screening v0.2148 | GPR161 |
Lilian Downie gene: GPR161 was added gene: GPR161 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GPR161 were set to PMID: 31609649 Phenotypes for gene: GPR161 were set to Medulloblastoma predisposition syndrome MIM#155255 Penetrance for gene: GPR161 were set to Incomplete Review for gene: GPR161 was set to RED Added comment: Increased risk of medulloblastoma at <3yrs Also identified in population and healthy parents Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | GREB1L |
Lilian Downie gene: GREB1L was added gene: GREB1L was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GREB1L were set to PMID: 29955957, 32585897 Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80 MIM#619274 Review for gene: GREB1L was set to GREEN Added comment: Congenital hearing impairment with cochlear abnormalities This gene also causes Renal hypodysplasia/aplasia 3 MIM#617805 with no clear difference in mutation spectrum Sources: Expert list |
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| BabyScreen+ newborn screening v0.2140 | LAMP2 |
Zornitza Stark edited their review of gene: LAMP2: Added comment: Treatment is currently symptomatic. On watch list with regards to specific treatment/clinical trials.; Changed rating: AMBER |
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| BabyScreen+ newborn screening v0.2134 | TRDN |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance.; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. |
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| BabyScreen+ newborn screening v0.2133 | TECRL |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. |
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| BabyScreen+ newborn screening v0.2131 | PRKG1 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Discussed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.2130 | MYH11 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair. Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not meet criteria for gNBS. |
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| BabyScreen+ newborn screening v0.2129 | LOX |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Discussed with paediatric cardiologist: variable penetrance and age of onset, does not fit with criteria for gNBS. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.2124 | CALM3 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Exclude for CPVT: association has moderate evidence, there are issues with penetrance, and treatment is generally only recommended in symptomatic individuals. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.2123 | CALM2 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals. |
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| BabyScreen+ newborn screening v0.2123 | CALM1 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals. |
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| BabyScreen+ newborn screening v0.2109 | CDCA8 |
Zornitza Stark gene: CDCA8 was added gene: CDCA8 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: CDCA8. Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CDCA8 were set to 28025328; 29546359 Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, MONDO:0018612, CDCA8-related Review for gene: CDCA8 was set to GREEN Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. Treatment: thyroxine Likely to be detected on standard NBS. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2077 | SGPL1 | Zornitza Stark Tag renal tag was added to gene: SGPL1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2068 | STK4 | Zornitza Stark reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2063 | SCARB2 |
Lilian Downie gene: SCARB2 was added gene: SCARB2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCARB2 were set to PMID: 34337151, PMID: 35346091, PMID: 26677510 Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure MIM#254900 Review for gene: SCARB2 was set to RED Added comment: Onset not <5 Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SGPL1 |
Lilian Downie gene: SGPL1 was added gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SGPL1 were set to PMID: 28165343 Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575 Review for gene: SGPL1 was set to RED Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?) Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SLC1A3 |
Lilian Downie gene: SLC1A3 was added gene: SLC1A3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC1A3 were set to PMID: 32754645 Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6 MIM#612656 Review for gene: SLC1A3 was set to RED Added comment: ataxia occurs with febrile illnesses Episodic attacks lasted 2 to 3 hours and were often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech Not consistently in children <5 and variable severity Suggested Rx acetazolamide Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SMARCD2 |
Lilian Downie gene: SMARCD2 was added gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377 Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475 Review for gene: SMARCD2 was set to GREEN Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects Rx bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STIM1 |
Lilian Downie gene: STIM1 was added gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041 Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783 Review for gene: STIM1 was set to GREEN Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta Rx bone marrow transpant Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STK4 |
Lilian Downie gene: STK4 was added gene: STK4 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STK4 were set to PMID: 22294732 Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868 Review for gene: STK4 was set to GREEN Added comment: primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect Rx bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STX16 |
Lilian Downie gene: STX16 was added gene: STX16 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) Publications for gene: STX16 were set to PMID: 33247854, PMID: 34477200, PMID: 29072892 Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB MIM#603233 Review for gene: STX16 was set to GREEN Added comment: characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH without other features of Albright hereditary osteodystrophy Rx Calcium, calcitriol, levothyroxine, growth hormone Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SYT2 |
Lilian Downie gene: SYT2 was added gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SYT2 were set to PMID: 32250532, 32776697 Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461 Review for gene: SYT2 was set to GREEN Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. Only report biallelic for newborn screening ? monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs Sources: Expert list |
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| BabyScreen+ newborn screening v0.2058 | SAMD9 |
Zornitza Stark gene: SAMD9 was added gene: SAMD9 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SAMD9 were set to 31306780 Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053 Review for gene: SAMD9 was set to GREEN Added comment: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection. Treatment: BMT. Non-genetic confirmatory testing: no. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | TNFRSF13B |
Lilian Downie gene: TNFRSF13B was added gene: TNFRSF13B was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TNFRSF13B were set to PMID: 31681716, PMID: 18981294 Phenotypes for gene: TNFRSF13B were set to Immunodeficiency, common variable, 2 MIM#240500 Review for gene: TNFRSF13B was set to RED Added comment: hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal. I think the age of onset is too variable . Rx immunoglobulin Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | TNFAIP3 |
Lilian Downie gene: TNFAIP3 was added gene: TNFAIP3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNFAIP3 were set to PMID: 31587140, PMID: 33101300 Phenotypes for gene: TNFAIP3 were set to Autoinflammatory syndrome, familial, Behcet-like 1 MIM#616744 Review for gene: TNFAIP3 was set to RED Added comment: Average age of onset 5yrs - too variable re age of onset. painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells. Treatment: Colchicine, glucocorticoid, mesalazine, cyclosporine, methotrexate, azathioprine, anakinra, rituximab, tocilizumab, infliximab Sources: Expert list |
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| BabyScreen+ newborn screening v0.2049 | RASGRP1 |
Zornitza Stark gene: RASGRP1 was added gene: RASGRP1 was added to Baby Screen+ newborn screening. Sources: Literature treatable, immunological tags were added to gene: RASGRP1. Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RASGRP1 were set to Immunodeficiency 64 (MIM#618534) Review for gene: RASGRP1 was set to GREEN Added comment: Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity. Severe disorder, fatal outcomes reported in childhood. Treatment: BMT. Non-genetic confirmatory testing: no. Sources: Literature |
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| BabyScreen+ newborn screening v0.2042 | OTULIN |
Zornitza Stark gene: OTULIN was added gene: OTULIN was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: OTULIN. Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 Review for gene: OTULIN was set to GREEN Added comment: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection. Onset is generally in infancy. Treatment: inflixiimab, anakinra, etanercept, corticosteroids. Non-genetic confirmatory testing: no. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2038 | NFKBIA |
Zornitza Stark gene: NFKBIA was added gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: NFKBIA. Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132 Review for gene: NFKBIA was set to GREEN Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual). Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity. The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands). Onset is generally in infancy. Treatment: BMT. Non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v0.2030 | MTHFD1 |
Zornitza Stark gene: MTHFD1 was added gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological, haematological tags were added to gene: MTHFD1. Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFD1 were set to 32414565; 19033438 Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780 Review for gene: MTHFD1 was set to GREEN Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models 7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites. Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases. Treatment: hydroxocobalamin, folinic acid and betaine Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF Sources: Expert list |
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| BabyScreen+ newborn screening v0.2026 | MALT1 |
Zornitza Stark gene: MALT1 was added gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MALT1. Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468 Review for gene: MALT1 was set to GREEN Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency. Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains. All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation. Treatment: prophylactic antibiotics, IVIG, BMT. Non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v0.2022 | LRBA |
Zornitza Stark gene: LRBA was added gene: LRBA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: LRBA. Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRBA were set to 22608502; 22721650; 25468195; 26206937; 33155142; 31887391 Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700 Review for gene: LRBA was set to GREEN Added comment: Well established gene-disease association. Generally childhood onset with recurrent infections and autoimmune phenomena. Treatment: abatacept, BMT. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2020 | LIG1 |
Zornitza Stark gene: LIG1 was added gene: LIG1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: LIG1. Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG1 were set to 30395541 Phenotypes for gene: LIG1 were set to Immunodeficiency 96, MIM# 619774 Review for gene: LIG1 was set to GREEN Added comment: Established gene-disease association. Onset is generally in early childhood. Presents with recurrent severe infections. Treatment: IVIG, BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, complete blood count Sources: Expert list |
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| BabyScreen+ newborn screening v0.2007 | IL2RA |
Zornitza Stark gene: IL2RA was added gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL2RA. Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367 Review for gene: IL2RA was set to GREEN Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation. At least 4 unrelated families reported. Treatment: rapamycin, bone marrow transplant. Confirmatory non-genetic testing: flow cytometric analysis. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2005 | IL21R |
Zornitza Stark gene: IL21R was added gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL21R. Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207 Review for gene: IL21R was set to GREEN Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Onset: infancy/early childhood. Treatment: BMT. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2001 | IKZF1 |
Zornitza Stark gene: IKZF1 was added gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873 Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset. PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation. Included primarily for LoF phenotype. Treatment: IVIG and BMT. Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.1993 | IFITM5 |
Zornitza Stark gene: IFITM5 was added gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list 5'UTR, treatable, skeletal tags were added to gene: IFITM5. Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609 Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967 Review for gene: IFITM5 was set to GREEN Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316). Variable severity, including within families. However, severe perinatal presentations reported. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1991 | ICOS |
Zornitza Stark gene: ICOS was added gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: ICOS. Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594 Review for gene: ICOS was set to GREEN Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models. Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion. Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA. Congenital onset. Treatment: replacement immunoglobulin treatment, bone marrow transplant. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TRNT1 |
Lilian Downie gene: TRNT1 was added gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905 Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084 Review for gene: TRNT1 was set to AMBER Added comment: Onset infancy Strong gene disease association Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013). Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR. DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1977 | HSD11B2 |
Zornitza Stark gene: HSD11B2 was added gene: HSD11B2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: HSD11B2. Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025 Review for gene: HSD11B2 was set to GREEN Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone. More than 10 unrelated families reported. Onset is usually in infancy or early childhood. Non-genetic confirmatory testing: aldosterone, renin, potassium levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.1975 | HOGA1 |
Zornitza Stark gene: HOGA1 was added gene: HOGA1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: HOGA1. Mode of inheritance for gene: HOGA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HOGA1 were set to 20797690; 21896830; 22391140 Phenotypes for gene: HOGA1 were set to Hyperoxaluria, primary, type III MIM#613616 Review for gene: HOGA1 was set to GREEN Added comment: Well-established association with primary hyperoxaluria type III. c.700+5G>T is a recurrent pathogenic variant in European populations (possibly founder) and has high frequency in gnomad (0.2-0.3%). Onset in infancy, progressive multi-system disorder. Treatment: pyridoxine, drinking large volumes, alkalinzation of urine, pyrophosphate-containing solutions, liver-kidney transplant Non-genetic confirmatory testing: urinary oxalate Sources: Expert list |
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| BabyScreen+ newborn screening v0.1973 | HELLS |
Zornitza Stark gene: HELLS was added gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911 Review for gene: HELLS was set to GREEN Added comment: Congenital onset. Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported. Treatment: bone marrow transplant. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1967 | GPIHBP1 |
Zornitza Stark gene: GPIHBP1 was added gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPIHBP1 were set to 31390500 Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome Review for gene: GPIHBP1 was set to GREEN Added comment: Well-established gene-disease association. Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. Treatment: volanesorsen, dietary fat restriction Non-genetic confirmatory testing: triglyceride level Sources: Expert list |
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| BabyScreen+ newborn screening v0.1965 | GHRHR |
Zornitza Stark gene: GHRHR was added gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GHRHR were set to 8528260; 10084571; 11232012 Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157 Review for gene: GHRHR was set to GREEN Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported. Non-genetic confirmatory testing: growth hormone stimulation test Sources: Expert list |
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| BabyScreen+ newborn screening v0.1958 | WDR72 | Zornitza Stark Phenotypes for gene: WDR72 were changed from Distal renal tubular acidosis to Amelogenesis imperfecta, type IIA3, MIM# 613211; Distal RTA MONDO:0015827 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1956 | WDR72 |
Zornitza Stark Tag treatable tag was added to gene: WDR72. Tag renal tag was added to gene: WDR72. |
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| BabyScreen+ newborn screening v0.1952 | WDR72 |
Lilian Downie gene: WDR72 was added gene: WDR72 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR72 were set to PMID: 30028003, PMID: 30779877, PMID:36836560, PMID: 33033857 Phenotypes for gene: WDR72 were set to Distal renal tubular acidosis Review for gene: WDR72 was set to GREEN Added comment: Amelogenesis imperecta - thickened and disoloured dental enamal with RTA Reduced penetrance or variable expression? Some patients only have the tooth phenotype... Presents with polyuria and growth restriction Treat with oral alkali replacement therapy, potassium chloride Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | WIPF1 |
Lilian Downie gene: WIPF1 was added gene: WIPF1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WIPF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WIPF1 were set to PMID: 27742395, PMID: 30450104, PMID: 22231303 Phenotypes for gene: WIPF1 were set to Wiskott-Aldrich syndrome 2 MIM#614493 Review for gene: WIPF1 was set to GREEN Added comment: Infant onset recurrent infections, thrombycytopenia and eczema Immunology testing to correlate Treatment/cure with bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | WNK4 |
Lilian Downie gene: WNK4 was added gene: WNK4 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WNK4 were set to PMID: 22073419, PMID: 31795491, PMID: 10869238, Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB MIM#614491 Review for gene: WNK4 was set to GREEN Added comment: Hyperkalaemia and hypertension Hypercalciuria Hypocalcaemia Decreased bone mineral density Renal calcium stones Treatable with thiazide diuretics Variable age of onset from infancy to adulthood but highly effective treatment so leaning toward include. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1951 | FOLR1 |
Zornitza Stark gene: FOLR1 was added gene: FOLR1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: FOLR1. Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOLR1 were set to 19732866; 30420205; 27743887 Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068 Review for gene: FOLR1 was set to GREEN Added comment: Folate is a neurotransmitter precursor. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function. Treatment: folinic acid Non-genetic confirmatory testing: cerebrospinal fluid 5-methyltetrahydrofolate level Sources: Expert list |
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| BabyScreen+ newborn screening v0.1949 | FCHO1 |
Zornitza Stark gene: FCHO1 was added gene: FCHO1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: FCHO1. Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FCHO1 were set to 32098969; 30822429 Phenotypes for gene: FCHO1 were set to Immunodeficiency 76, MIM# 619164 Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data. Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features. Treatment: bone marrow transplant. Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, immunoglobulin levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.1935 | C17orf62 |
Zornitza Stark gene: C17orf62 was added gene: C17orf62 was added to Baby Screen+ newborn screening. Sources: Expert Review new gene name, treatable, immunological tags were added to gene: C17orf62. Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984 Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease 5, autosomal recessive, MIM# 618935 Review for gene: C17orf62 was set to GREEN Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name) Primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Haematopoietic bone marrow transplant is curative. Non-genetic confirmatory assay: dihydrorhodamine assay Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1933 | CYB561 |
Zornitza Stark gene: CYB561 was added gene: CYB561 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYB561 were set to 29343526; 31822578 Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182 Review for gene: CYB561 was set to GREEN Added comment: Three families reported. Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood. Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa) Non-genetic confirmatory testing: plasma norepinephrine, epinephrine, dopamine Sources: Expert list |
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| BabyScreen+ newborn screening v0.1929 | CORO1A |
Zornitza Stark gene: CORO1A was added gene: CORO1A was added to gNBS. Sources: Expert list Mode of inheritance for gene: CORO1A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CORO1A were set to Immunodeficiency 8 MIM# 615401 Review for gene: CORO1A was set to GREEN Added comment: 3 unrelated families and 1 unrelated individual reported with bi-allelic (deletion, missense, insertion) variants, resulting in premature stop codons and truncated protein/ alter a highly conserved residue in binding domain; one mouse model All patients displayed T−B+NK+ SCID or CID presenting in early-onset recurrent infections and additional features that included EBV-associated lymphoproliferative disease and low immunoglobulin levels. Congenital onset. Treatment: bone marrow transplant Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile Sources: Expert list |
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| BabyScreen+ newborn screening v0.1872 | HMGCS2 |
Lilian Downie gene: HMGCS2 was added gene: HMGCS2 was added to gNBS. Sources: Expert list Mode of inheritance for gene: HMGCS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HMGCS2 were set to PMID: 32259399, 32470406 Phenotypes for gene: HMGCS2 were set to HMG-CoA synthase-2 deficiency MIM#605911 Penetrance for gene: HMGCS2 were set to Incomplete Review for gene: HMGCS2 was set to AMBER Added comment: Metabolic disorder; patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. Recover completely between illnesses, do develop fatty liver. ?incomplete penetrance or variable age of onset On GUARDIAN and Rx Genes Rx IV glucose during acute episodes, avoid prolonged fasting Metabolic parameters are normal in between episodes, so no ability to do a confirmatory biochemical test. Pros: readily treatable if child has an episode Cons: unncessary worry as child may never have episode Super rare ?30 cases Discuss with JC? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1872 | TANGO2 | Zornitza Stark Phenotypes for gene: TANGO2 were changed from Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1865 | TANGO2 |
Ari Horton changed review comment from: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review; to: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 PMID: 35568137 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4–9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504–600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1865 | NKX2-5 | Ari Horton reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal onset cardiomyopathy, Congenital Heart Disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1865 | GATA4 | Ari Horton reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, Congenital Heart Disease, Arrhythmia, Extra-cardiac Manifestations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1843 | CAD |
Zornitza Stark gene: CAD was added gene: CAD was added to gNBS. Sources: Expert list treatable, metabolic tags were added to gene: CAD. Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAD were set to 28007989 Phenotypes for gene: CAD were set to Developmental and epileptic encephalopathy 50, MIM# 616457 Review for gene: CAD was set to GREEN Added comment: Developmental and epileptic encephalopathy-50 (DEE50) is an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia. Onset is within the first months or years of life. Affected children can have a favourable response to treatment with uridine, PMID 28007989 Sources: Expert list |
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| BabyScreen+ newborn screening v0.1834 | WT1 |
Zornitza Stark changed review comment from: Rated as 'moderate actionability' in paediatric patients by ClinGen. Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%. The goal of surveillance in individuals with a genetic predisposition to WT is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome. No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms. Penetrance is unclear. For review.; to: Rated as 'moderate actionability' in paediatric patients by ClinGen. Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%. The goal of surveillance in individuals with a genetic predisposition to WT is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome. No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms. |
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| BabyScreen+ newborn screening v0.1834 | GLA |
Zornitza Stark changed review comment from: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started.; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. Note ERT is licensed in Australia from age 7 years. However, carbamazepine relieves neuropathic pain, which has onset in early childhood. Overall, include. |
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| BabyScreen+ newborn screening v0.1833 | SMAD2 |
Zornitza Stark gene: SMAD2 was added gene: SMAD2 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, MIM# 619656 Review for gene: SMAD2 was set to GREEN Added comment: 9 individuals from 5 unrelated families reported with LDS phenotype. Gene-disease association rated 'moderate' by ClinGen but this gene is included in our diagnostic testing. LDS included in gNBS panel as in general medical actionability for the LDS group of disorders is considered established. Can manifest in early childhood. Treatment: different interventions, including beta-blockers, surgical and monitoring Non-genetic confirmatory test: characteristic clinical findings Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1821 | RET |
Zornitza Stark changed review comment from: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: actionable in first 5 years of life?; to: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: some actionability in first 5 years, variants can be stratified in terms of risk. |
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| BabyScreen+ newborn screening v0.1801 | MLH1 |
Zornitza Stark changed review comment from: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites; to: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites |
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| BabyScreen+ newborn screening v0.1781 | PRKG1 |
Zornitza Stark gene: PRKG1 was added gene: PRKG1 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: PRKG1. Mode of inheritance for gene: PRKG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PRKG1 were set to Aortic aneurysm, familial thoracic 8, MIM#615436 Penetrance for gene: PRKG1 were set to Incomplete Review for gene: PRKG1 was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1778 | LOX |
Zornitza Stark gene: LOX was added gene: LOX was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: LOX. Mode of inheritance for gene: LOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LOX were set to Aortic aneurysm, familial thoracic 10, MIM#617168 Penetrance for gene: LOX were set to Incomplete Review for gene: LOX was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1770 | DICER1 |
Zornitza Stark gene: DICER1 was added gene: DICER1 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: DICER1 were set to DICER1 syndrome, MONDO:0017288 Penetrance for gene: DICER1 were set to Incomplete Review for gene: DICER1 was set to AMBER Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen. A multiple registry study examining neoplasm incidence in a cohort containing 102 non-probands with DICER1 pathogenic variants (3,344 person-years of observation in non-probands) found that by age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of non-probands had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of non-probands had developed a neoplasm (females, 26.5%; males, 10.2%). Most individuals with pathogenic variants in DICER1 are healthy or have only minor DICER1-associaited conditions. The most severe manifestations tend to present in early childhood with adulthood characterized by good health. The majority of tumors in individuals with DICER1 pathogenic variants occur in individuals younger than 40. Many of these tumors typically only occur in childhood, including: PPB (before age 7), CN (before age 4), CBME typically occurs in young children, pituitary blastoma (before age 2), and childhood pineoblastoma (only one has been reported associated with a DICER1 mutation). Surveillance recommendations: In order to detect pulmonary cysts or PPB (one of the most important causes of DICER1-associated morbidity and mortality), chest x-rays are recommended every 6 months from birth to through age 7 years and then annually from 8-12 years. A chest computed tomography (CT) (with efforts to minimize radiation) should be obtained by 9 months of age, preferably between 3 and 6 months of age and repeated at approximately 2.5 years of age. Abdominal ultrasound is recommended for the detection in infancy or at the time of the first chest CT then every 6-12 months until at least 8 years of age. Annual ultrasound may be considered until 12 years of age. Beginning at ages 8-10 females should receive pelvic ultrasound performed in conjunction with abdominal ultrasound (every 6-12 months) until at least age 40 or as needed for signs and symptoms. Individuals should undergo thyroid ultrasound with assessment for regional adenopathy every 2 to 3 years starting at age 8 or as needed for signs and symptoms. An annual routine dilated ophthalmologic exam with visual acuity screening is recommended from age 3 to at least age 10 for detection of CBME. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1750 | PRKAR1A | Zornitza Stark Phenotypes for gene: PRKAR1A were changed from Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Carney complex, type 1, MIM# 160980; Myxoma, intracardiac, MIM# 255960; Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489 to Carney complex, type 1, MIM# 160980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1736 | TECRL |
Zornitza Stark gene: TECRL was added gene: TECRL was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: TECRL. Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021 Review for gene: TECRL was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1734 | CALM3 |
Zornitza Stark gene: CALM3 was added gene: CALM3 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM3. Mode of inheritance for gene: CALM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM3 were set to Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782 Penetrance for gene: CALM3 were set to Incomplete Review for gene: CALM3 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1732 | CALM2 |
Zornitza Stark gene: CALM2 was added gene: CALM2 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM2. Mode of inheritance for gene: CALM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM2 were set to Catecholaminergic polymorphic ventricular tachycardia MONDO:0017990 Review for gene: CALM2 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1730 | CALM1 |
Zornitza Stark gene: CALM1 was added gene: CALM1 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM1. Mode of inheritance for gene: CALM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM1 were set to Ventricular tachycardia, catecholaminergic polymorphic, 4, MIM# 614916 Penetrance for gene: CALM1 were set to Incomplete Review for gene: CALM1 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1728 | RPE65 |
Zornitza Stark gene: RPE65 was added gene: RPE65 was added to gNBS. Sources: ClinGen for review, treatable, ophthalmological tags were added to gene: RPE65. Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794 Review for gene: RPE65 was set to GREEN Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision. In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood. In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups. LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes). For review: availability of therapy? Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1712 | SLC12A1 |
Zornitza Stark Tag treatable tag was added to gene: SLC12A1. Tag renal tag was added to gene: SLC12A1. |
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| BabyScreen+ newborn screening v0.1706 | KCNJ1 |
Zornitza Stark Tag treatable tag was added to gene: KCNJ1. Tag renal tag was added to gene: KCNJ1. |
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| BabyScreen+ newborn screening v0.1701 | GLA |
Zornitza Stark changed review comment from: For review: screen only for males or include both?; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. |
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| BabyScreen+ newborn screening v0.1687 | CTNS | Zornitza Stark Tag renal tag was added to gene: CTNS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1682 | COL4A3 |
Zornitza Stark Tag treatable tag was added to gene: COL4A3. Tag renal tag was added to gene: COL4A3. |
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| BabyScreen+ newborn screening v0.1681 | COL4A4 |
Zornitza Stark Tag treatable tag was added to gene: COL4A4. Tag renal tag was added to gene: COL4A4. |
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| BabyScreen+ newborn screening v0.1681 | COL4A4 |
Zornitza Stark changed review comment from: Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Males with XLAS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. Guidelines differ slightly for the initiation of treatment in females with XLAS; one guideline recommends initiation of treatment at onset of microalbuminuria while a second recommends initiation at onset of microalbuminuria, hypertension, or renal impairment.; to: Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Individuals with AR AS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. |
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| BabyScreen+ newborn screening v0.1681 | COL4A5 |
Zornitza Stark changed review comment from: Well established gene-disease association. Natural history: In males, truncating variants in COL4A5 are associated with an earlier age at onset of kidney failure; risk of ESRD before age 30 is estimated as 90% for large rearrangements and pathogenic nonsense and frameshift variants, 70% for splice variants, and 50% for missense variants. In males, progressive SNHL is usually present by late childhood or early adolescence, and interior lenticous typically becomes apparent in late adolescence or early adulthood. In females, renal disease ranges from asymptomatic disease to lifelong microhematuria to renal failure at a young age. In females, progressive SNHL is typically later in life, lenticonus may not occur, and central retinopathy is rare. Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Males with XLAS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. Guidelines differ slightly for the initiation of treatment in females with XLAS; one guideline recommends initiation of treatment at onset of microalbuminuria while a second recommends initiation at onset of microalbuminuria, hypertension, or renal impairment. For review: screen both males and females?; to: Well established gene-disease association. Natural history: In males, truncating variants in COL4A5 are associated with an earlier age at onset of kidney failure; risk of ESRD before age 30 is estimated as 90% for large rearrangements and pathogenic nonsense and frameshift variants, 70% for splice variants, and 50% for missense variants. In males, progressive SNHL is usually present by late childhood or early adolescence, and interior lenticous typically becomes apparent in late adolescence or early adulthood. In females, renal disease ranges from asymptomatic disease to lifelong microhematuria to renal failure at a young age. In females, progressive SNHL is typically later in life, lenticonus may not occur, and central retinopathy is rare. Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Males with XLAS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. Guidelines differ slightly for the initiation of treatment in females with XLAS; one guideline recommends initiation of treatment at onset of microalbuminuria while a second recommends initiation at onset of microalbuminuria, hypertension, or renal impairment. |
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| BabyScreen+ newborn screening v0.1681 | COL4A5 | Zornitza Stark Tag renal tag was added to gene: COL4A5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1675 | BSND | Zornitza Stark Tag renal tag was added to gene: BSND. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1632 | TCN2 | John Christodoulou reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32841161, PMID: 33685478; Phenotypes: failure to thrive, megaloblastic anaemia, recurrent infections, ID, vomiting, diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1632 | SLC25A19 | John Christodoulou reviewed gene: SLC25A19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31095747; Phenotypes: recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, polyneuropathy, ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1632 | ATP6V1B1 | Zornitza Stark Tag renal tag was added to gene: ATP6V1B1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1632 | ATP6V0A4 | Zornitza Stark Tag renal tag was added to gene: ATP6V0A4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1623 | PRKAR1A | Zornitza Stark Phenotypes for gene: PRKAR1A were changed from Carney complex to Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Carney complex, type 1, MIM# 160980; Myxoma, intracardiac, MIM# 255960; Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1621 | PRKAR1A | Zornitza Stark reviewed gene: PRKAR1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800, Carney complex, type 1, MIM# 160980, Myxoma, intracardiac, MIM# 255960, Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1591 | PQBP1 | Zornitza Stark Phenotypes for gene: PQBP1 were changed from Mental retardation to Renpenning syndrome, MIM#309500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1589 | PQBP1 | Zornitza Stark reviewed gene: PQBP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renpenning syndrome, MIM#309500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1587 | PMP22 | Zornitza Stark Phenotypes for gene: PMP22 were changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, type 1A, MIM# 118220; Charcot-Marie-Tooth disease, type 1E, MIM# 118300; Dejerine-Sottas disease, MIM# 145900; Neuropathy, recurrent, with pressure palsies 162500; Roussy-Levy syndrome 180800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1585 | PMP22 | Zornitza Stark reviewed gene: PMP22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 1A, MIM# 118220, Charcot-Marie-Tooth disease, type 1E, MIM# 118300, Dejerine-Sottas disease, MIM# 145900, Neuropathy, recurrent, with pressure palsies 162500, Roussy-Levy syndrome 180800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1564 | PKD2 |
Zornitza Stark Tag for review tag was added to gene: PKD2. Tag treatable tag was added to gene: PKD2. Tag renal tag was added to gene: PKD2. |
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| BabyScreen+ newborn screening v0.1564 | PKD2 |
Zornitza Stark changed review comment from: Well established gene-disease association. Onset of renal failure is generally in adulthood, though cysts are apparent earlier. Treatment: Tolvaptan; to: Well established gene-disease association. Onset of renal failure is generally in late adulthood, though cysts are apparent earlier. Treatment: Tolvaptan |
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| BabyScreen+ newborn screening v0.1562 | PKD1 |
Zornitza Stark Tag for review tag was added to gene: PKD1. Tag treatable tag was added to gene: PKD1. Tag renal tag was added to gene: PKD1. |
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| BabyScreen+ newborn screening v0.1536 | TBX19 | Seb Lunke reviewed gene: TBX19: Rating: GREEN; Mode of pathogenicity: None; Publications: 30086867; Phenotypes: Adrenocorticotropic hormone deficiency, 201400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1510 | STAT3 | Seb Lunke Phenotypes for gene: STAT3 were changed from Hyper-IgE recurrent infection syndrome to Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1509 | STAR | Seb Lunke Phenotypes for gene: STAR were changed from Congenital lipoid adrenal hyperplasia, MIM#201710 to Congenital lipoid adrenal hyperplasia, MIM#201710 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1508 | STAR | Seb Lunke reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1469 | ORAI1 |
Zornitza Stark gene: ORAI1 was added gene: ORAI1 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: ORAI1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ORAI1 were set to Immunodeficiency 9, MIM# 612782 Review for gene: ORAI1 was set to GREEN Added comment: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a slowly progressive myopathy (tubular aggregate myopathy/TAM) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy) Included here for AR disease. Onset is in newborn period. Life-threatening. Treatment: BMT. Non-genetic confirmatory testing: T cell proliferation assay Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1458 | REN | Zornitza Stark Marked gene: REN as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1458 | REN | Zornitza Stark Gene: ren has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1458 | REN | Zornitza Stark Phenotypes for gene: REN were changed from Renal tubular dysgenesis to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1457 | REN | Zornitza Stark Mode of inheritance for gene: REN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1456 | REN |
Zornitza Stark changed review comment from: Established gene-disease association. Presents as fetal anuria leading to perinatal death. No specific treatment.; to: Established gene-disease association. Bi-allelic LOF variants cause renal tubular dysgenesis, which presents as fetal anuria leading to perinatal death.. Mono-allelic variants, likely through a different mechanism (mostly missense) cause tubulointerstitial disease. More severe phenotype associated with variants that are located in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). No specific treatment for either. |
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| BabyScreen+ newborn screening v0.1456 | REN | Zornitza Stark Classified gene: REN as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1456 | REN | Zornitza Stark Gene: ren has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1455 | REN | Zornitza Stark reviewed gene: REN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1451 | CIITA |
Zornitza Stark gene: CIITA was added gene: CIITA was added to gNBS. Sources: Expert Review Mode of inheritance for gene: CIITA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CIITA were set to Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920 Review for gene: CIITA was set to GREEN Added comment: 13 individuals of 11 unrelated families; two mouse models. Homozygous and compound heterozygous variants were identified in these individuals (missense, nonsense and splicing) resulting in premature stop codon and truncated protein, or inactive protein. Affected individuals typically present in infancy with severe (recurrent) respiratory and gastrointestinal tract infections and defective MHC II expression in PBMCs Treatment: BMT. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1449 | RFXAP |
Zornitza Stark gene: RFXAP was added gene: RFXAP was added to gNBS. Sources: Expert Review Mode of inheritance for gene: RFXAP was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RFXAP were set to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920 Review for gene: RFXAP was set to GREEN Added comment: 9 unique RFXAP variants in 12 unrelated individuals have been reported; one mouse model The most frequent variant is a deletion c. delG484fsX525 which has been identified in 4 individuals of different origins (North African, Turkish and East Asian). Typically presents in infancy with recurrent bacterial infections, severe diarrhoea and failure to thrive. Treatment: BMT. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1447 | RFX5 |
Zornitza Stark gene: RFX5 was added gene: RFX5 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: RFX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RFX5 were set to Bare lymphocyte syndrome, type II, complementation group C MIM# 209920; Bare lymphocyte syndrome, type II, complementation group E MIM# 209920 Review for gene: RFX5 was set to GREEN Added comment: Bare lymphocyte syndrome, type II, complementation group C 9 individuals from 8 unrelated families; multiple mouse models Homozygous and Compound heterozygous (Nonsense, missense, splice site, single bp del) variants were reported resulting in truncated protein and loss of function. All individuals presented with recurrent lower respiratory tract infection early in life, low CD4+ cells and/or failure to thrive, chronic diarrhoea, hepatosplenomegaly and low Ig levels. ---------- Bare lymphocyte syndrome, type II, complementation group E 2 siblings (twins) reported with RPX5 variants and new BLS group E phenotype; multiple functional studies Identified homozygous missense variant (R149Q) which resulted in altered DNA-binding domain and loss of function. These histo-identical twin brothers had normal numbers of CD4 + cells and are able to mount both cellular and humoral immune responses. They displayed absence of MHC class II surface expression on B cells and mononuclear cells. Presentation is typically in infancy. Treatment: BMT. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1425 | RYR1 |
Zornitza Stark changed review comment from: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). For review.; to: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). |
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| BabyScreen+ newborn screening v0.1417 | SLC3A1 |
Zornitza Stark Tag for review tag was added to gene: SLC3A1. Tag treatable tag was added to gene: SLC3A1. Tag renal tag was added to gene: SLC3A1. |
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| BabyScreen+ newborn screening v0.1389 | SLC4A1 |
Zornitza Stark Tag treatable tag was added to gene: SLC4A1. Tag renal tag was added to gene: SLC4A1. |
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| BabyScreen+ newborn screening v0.1381 | RRM2B | Zornitza Stark Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075; Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, MIM# 268315 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1379 | RRM2B | Zornitza Stark reviewed gene: RRM2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) MIM#612075, Mitochondrial DNA depletion syndrome 8B (MNGIE type) MIM#612075, Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, MIM# 268315; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1344 | SLC4A1 | Seb Lunke Phenotypes for gene: SLC4A1 were changed from Spherocytosis to Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1341 | SLC4A1 | Seb Lunke reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31600044; Phenotypes: Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1340 | SLC46A1 |
Seb Lunke changed review comment from: Established gene-disease association. Childhood onset, metabolic disorders Treatment: 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin) or the active isomer of 5-formylTHF (Isovorin or Fusilev) Parenteral (intramuscular) or high-dose oral Non-genetic confirmatory test: CSF and serum folate levels; to: Established gene-disease association. Childhood onset, metabolic disorder Treatment: 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin) or the active isomer of 5-formylTHF (Isovorin or Fusilev) Parenteral (intramuscular) or high-dose oral Non-genetic confirmatory test: CSF and serum folate levels |
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| BabyScreen+ newborn screening v0.1340 | SLC46A1 |
Seb Lunke changed review comment from: Established gene-disease association. Childhood onset, Treatment: 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin) or the active isomer of 5-formylTHF (Isovorin or Fusilev) Parenteral (intramuscular) or high-dose oral Non-genetic confirmatory test: CSF and serum folate levels; to: Established gene-disease association. Childhood onset, metabolic disorders Treatment: 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin) or the active isomer of 5-formylTHF (Isovorin or Fusilev) Parenteral (intramuscular) or high-dose oral Non-genetic confirmatory test: CSF and serum folate levels |
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| BabyScreen+ newborn screening v0.1294 | HNF4A | Zornitza Stark Phenotypes for gene: HNF4A were changed from Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850 to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850; MODY, type I, OMIM # 125850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1292 | HNF4A | Zornitza Stark reviewed gene: HNF4A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026, MODY, type I, OMIM # 125850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1272 | HSD3B2 | John Christodoulou reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26079780, PMID: 33757164; Phenotypes: adrenal insufficiency, hypspadias, pseudohermaphroditism in males, mild masculinization in females; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1272 | HGD | John Christodoulou reviewed gene: HGD: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 34344451, PMID: 12501223, PMID: 12501223; Phenotypes: progressive arthritis, progressive calcific cardiac valve damage, renal stones; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1268 | HSD3B2 | Zornitza Stark reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM# 201810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1261 | SLC4A4 | Seb Lunke Phenotypes for gene: SLC4A4 were changed from Renal tubular acidosis, proximal, with ocular abnormalities to Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1260 | SLC4A4 | Seb Lunke reviewed gene: SLC4A4: Rating: RED; Mode of pathogenicity: None; Publications: 24978391; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1154 | GRHPR | John Christodoulou reviewed gene: GRHPR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301742; Phenotypes: nephrolithiasis, haematuria, renal colic, obstruction of the urinary tract, Nephrocalcinosis, End-stage renal disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1094 | SLC18A2 |
Seb Lunke changed review comment from: Established gene-disease association. Childhood onset neurological condition. Treatment: L-dopa resulted in severe exacerbation of the symptoms. Dopamine receptor agonist (pramipexole) resulted in improvement in symptoms. Earlier treatment more beneficial. Evidence from single family with benefits shown in 4 affected children. Non-genetic confirmatory test: blood pressure measurement and sodium, potassium, aldosterone, renin levels; to: Established gene-disease association. Childhood onset neurological condition. Treatment: L-dopa resulted in severe exacerbation of the symptoms. Dopamine receptor agonist (pramipexole) resulted in improvement in symptoms. Earlier treatment more beneficial. Evidence from single family with benefits shown in 4 affected children. Non-genetic confirmatory test: whole blood serotonin level |
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| BabyScreen+ newborn screening v0.1040 | FAM58A | Zornitza Stark Phenotypes for gene: FAM58A were changed from Syndactyly - telecanthus - anogenital and renal malformations to syndactyly-telecanthus-anogenital and renal malformations syndrome MONDO:0010408 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1038 | FAM58A | Zornitza Stark reviewed gene: FAM58A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: syndactyly-telecanthus-anogenital and renal malformations syndrome MONDO:0010408; Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1007 | FLCN |
Zornitza Stark changed review comment from: Well established gene-disease association. Typically manifests in adulthood, therefore predictive testing usually offered in adolescence with surveillance thereafter. For review.; to: Well established gene-disease association. Typically manifests in adulthood, therefore predictive testing usually offered in adolescence with surveillance thereafter. Renal cancer age of onset ~50 years. For review. |
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| BabyScreen+ newborn screening v0.995 | FOXI1 | Zornitza Stark Phenotypes for gene: FOXI1 were changed from sensorineural deafness and distal renal tubular acidosis to autosomal recessive distal renal tubular acidosis MONDO:0018440 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.993 | FOXI1 | Zornitza Stark reviewed gene: FOXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.975 | EYA1 | Zornitza Stark Phenotypes for gene: EYA1 were changed from Branchiootorenal syndrome to Anterior segment anomalies with or without cataract MIM#602588; Branchiootic syndrome 1 MIM#602588; Branchiootorenal syndrome 1, with or without cataracts MIM#113650 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.973 | EYA1 | Zornitza Stark reviewed gene: EYA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment anomalies with or without cataract MIM#602588, Branchiootic syndrome 1 MIM#602588, Branchiootorenal syndrome 1, with or without cataracts MIM#113650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.950 | GLA | John Christodoulou reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30017653; Phenotypes: neuropathic pain, cardiomyopathy, cataract, agniokeratomata, deafness, hypohidrosis, stroke, renal failure; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.914 | ENG |
Zornitza Stark changed review comment from: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). For review.; to: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). Management guidelines also suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.889 | DOCK8 | Zornitza Stark reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive, MIM# 243700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.862 | ACVRL1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available. However, management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695.; to: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available but emboli zing AVMs alters their natural history. Management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.787 | PCBD1 |
John Christodoulou changed review comment from: is on the current VCGS newborn screening panel; to: is on the current VCGS newborn screening panel by virtue of phenylalanine being the primary first tier metabolite that is analysed. Hyperphenylalaninaemia when present in the newborn is transient. There doesn’t appear to be cognitive impairment if untreated, but some individuals develop diabetes and/or mild hypomagnesaemia later in adolescence. There does not appear to be any evidence that any treatments in infancy would have an effect on these two late effects. See: PMID: 32456656 So, I think we can take this one off the list. |
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| BabyScreen+ newborn screening v0.719 | PDHA1 | John Christodoulou reviewed gene: PDHA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: lactic acidosis, porencephaly, ID, seizures, dystonia; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.706 | SIX1 | Seb Lunke Phenotypes for gene: SIX1 were changed from Branchiootorenal syndrome to Branchiootic syndrome 3, MIM# 608389 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.704 | SIL1 | Seb Lunke Phenotypes for gene: SIL1 were changed from Marinesco-Sjogren syndrome to Marinesco-Sjogren syndrome, MIM#248800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.702 | SIL1 | Seb Lunke reviewed gene: SIL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Marinesco-Sjogren syndrome, MIM#248800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.673 | DPAGT1 |
Zornitza Stark changed review comment from: Bi-allelic variants cause either multi-system CDG or congenital myasthenia graves. Difficult to predict phenotype from genotype but MG may be responsive to treatment. Phenotype may already be apparent in newborn period so clinical correlation possible.; to: Bi-allelic variants cause either multi-system CDG or congenital myasthenia gravis. Difficult to predict phenotype from genotype but MG may be responsive to treatment. Phenotype may already be apparent in newborn period so clinical correlation possible. |
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| BabyScreen+ newborn screening v0.664 | FUCA1 |
Zornitza Stark changed review comment from: Non-genetic confirmatory testing: fucosidase activity in serum or plasma For review regarding utility of BMT.; to: Non-genetic confirmatory testing: fucosidase activity in serum or plasma For review regarding utility of BMT: include, uncertain if pre-symptomatic BMT may have better outcomes than currently reported. |
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| BabyScreen+ newborn screening v0.664 | ETFB |
Zornitza Stark changed review comment from: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis; to: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis Predominantly neonatal onset. |
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| BabyScreen+ newborn screening v0.662 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. Include bi-allelic disease in gNBS. Continue considering if and when mono-allelic disease should be included. |
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| BabyScreen+ newborn screening v0.661 | DPAGT1 |
Zornitza Stark changed review comment from: Bi-allelic variants cause either multi-system CDG or congenital myasthenia graves. Difficult to predict phenotype from genotype but MG may be responsive to treatment. For review.; to: Bi-allelic variants cause either multi-system CDG or congenital myasthenia graves. Difficult to predict phenotype from genotype but MG may be responsive to treatment. Phenotype may already be apparent in newborn period so clinical correlation possible. |
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| BabyScreen+ newborn screening v0.654 | CLDN19 | Zornitza Stark Phenotypes for gene: CLDN19 were changed from Hypomagnesemia 5, renal, with ocular involvement to Deafness, autosomal recessive 116 MIM#619093 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.603 | CD79A |
Zornitza Stark changed review comment from: At least 5 unrelated families. Presents in infancy. Treatment: immunoglobulin replacement.; to: At least 5 unrelated families. Presents in infancy with severe recurrent infections. Treatment: immunoglobulin replacement. |
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| BabyScreen+ newborn screening v0.602 | VIPAS39 | Zornitza Stark Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction and cholestasis to Arthrogryposis, renal dysfunction, and cholestasis MIM#613404 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.599 | VIPAS39 | Zornitza Stark reviewed gene: VIPAS39: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis MIM#613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.588 | VIPAS39 | Lilian Downie reviewed gene: VIPAS39: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35761207; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis MIM#613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.586 | COQ7 |
Zornitza Stark changed review comment from: Four families reported. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.; to: Four families reported only. Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations. However this advice applies to the whole group of related conditions, and data on this particular condition in terms of natural history and response to treatment is currently limited. |
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| BabyScreen+ newborn screening v0.583 | FUCA1 | John Christodoulou reviewed gene: FUCA1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33266441; Phenotypes: neurodegneration, coarse facial features, grow retardation, dysostosis multiplex, angiokeratomata, recurrent URTIs; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.562 | CA2 | Zornitza Stark Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.561 | CA2 | Zornitza Stark reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.553 | GATA3 | Zornitza Stark reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.541 | GATA3 | Alison Yeung reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.529 | CYP11A1 | Zornitza Stark reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.528 | CYP11B1 | Zornitza Stark reviewed gene: CYP11B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, MIM# 202010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CYP17A1 | John Christodoulou reviewed gene: CYP17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: congenital adrenal hyperplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CYP11B1 | John Christodoulou reviewed gene: CYP11B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27928728; Phenotypes: congenital adrenal hyperplasia, aldosteronism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CYP11A1 | John Christodoulou reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25096886; Phenotypes: congenital adrenal hyperplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CUBN | John Christodoulou commented on gene: CUBN: defect of intestinal vitamin B12 absorption; treatable with pharmacological doses of parenteral vitamin B12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CTNS | John Christodoulou reviewed gene: CTNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi tubulopathy, photophobia, chronic renal failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | CPS1 | John Christodoulou reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neonatal hyperammonaemia and subsequent recurrent episodes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.523 | VPS33B | Zornitza Stark Phenotypes for gene: VPS33B were changed from Arthrogryposis renal dysfunction cholestasis syndrome to Arthrogryposis, renal dysfunction, and cholestasis MIM#208085 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.503 | VPS33B | Lilian Downie reviewed gene: VPS33B: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 15052268, 15052268, 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis MIM#208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.502 | GAA | Alison Yeung reviewed gene: GAA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease II, Pompe disease, MIM# 232300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.490 | SACS | Seb Lunke reviewed gene: SACS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia, Charlevoix-Saguenay type MIM#270550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.490 | G6PC3 | Alison Yeung reviewed gene: G6PC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, severe congenital 4, autosomal recessive, MIM# 612541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.472 | OCRL | Zornitza Stark Phenotypes for gene: OCRL were changed from Lowe oculocerebrorenal syndrome to Dent disease 2, MIM# 300555; Lowe syndrome , MIM#309000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.462 | NR5A1 | Zornitza Stark Phenotypes for gene: NR5A1 were changed from 46, XX sex reversal 4, MIM# 617480; 46XY sex reversal 3, MIM# 612965 to Adrenocortical insufficiency, (MIM#612964) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.461 | NR5A1 | Zornitza Stark reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenocortical insufficiency, (MIM#612964); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.461 | NR0B1 | Zornitza Stark Phenotypes for gene: NR0B1 were changed from Congenital adrenal hypoplasia to Adrenal hypoplasia, congenital (MIM# 300200) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.460 | NR0B1 | Zornitza Stark reviewed gene: NR0B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hypoplasia, congenital (MIM# 300200); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.456 | NPHP3 | Zornitza Stark Phenotypes for gene: NPHP3 were changed from Nephronophthisis to Renal-hepatic-pancreatic dysplasia 1, MIM# 208540 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.455 | NPHP3 | Zornitza Stark reviewed gene: NPHP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal-hepatic-pancreatic dysplasia 1, MIM# 208540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.427 | NEK8 | Zornitza Stark reviewed gene: NEK8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.293 | SLC5A2 | Zornitza Stark Phenotypes for gene: SLC5A2 were changed from Renal glucosuria to Renal glucosuria, MIM# 233100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.290 | SLC5A2 | Zornitza Stark reviewed gene: SLC5A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal glucosuria, MIM# 233100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.274 | ETFA |
Zornitza Stark changed review comment from: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates, D,L-3-hydroxybutyrate Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis; to: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates, D,L-3-hydroxybutyrate (PMID 31904027) Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis |
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| BabyScreen+ newborn screening v0.274 | NR5A1 | David Amor reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenocortical insufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.274 | NR0B1 | David Amor reviewed gene: NR0B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital adrenal hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.274 | NEK8 | David Amor reviewed gene: NEK8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal-hepatic-pancreatic dysplasia 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.270 | ZNF469 |
Lilian Downie changed review comment from: Well established gene-disease association. Severe, causes blindness in the majority in early childhood but variable. Connective tissue disease spectrum. Can cause ocular rupture. Treatment: lifestyle modification (rupture can occur from minor trauma), protective eyewear and avoidance of contact sports and activities, different surgical techniques have been tried in patients with variable success; to: Well established gene-disease association. Severe, causes blindness in the majority in early childhood but variable. Corneal thinning. Connective tissue disease spectrum, can have systemic features. Ocular rupture causes blindness. Treatment: lifestyle modification (rupture can occur from minor trauma), protective eyewear and avoidance of contact sports and activities, different surgical techniques have been tried in patients with variable success |
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| BabyScreen+ newborn screening v0.270 | ZNF469 |
Lilian Downie changed review comment from: Well established gene-disease association. Severe, can cause blindness in early childhood but variable. Connective tissue disease spectrum. Can cause ocular rupture. Treatment: no, only lifestyle modification (rupture can occur from minor trauma) and protective eyewear.; to: Well established gene-disease association. Severe, causes blindness in the majority in early childhood but variable. Connective tissue disease spectrum. Can cause ocular rupture. Treatment: lifestyle modification (rupture can occur from minor trauma), protective eyewear and avoidance of contact sports and activities, different surgical techniques have been tried in patients with variable success |
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| BabyScreen+ newborn screening v0.270 | BTD |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable severity and age of presentation, predominantly with cutaneous and neurologic abnormalities Treatment: biotin Non-genetic confirmatory testing: biotinidase enzyme activity in serum or plasma; to: Well established gene-disease association. Variable severity and age of presentation, predominantly with cutaneous and neurologic abnormalities. Phenotype can be difficult to predict from genotype, however note currently included in tNBS. Treatment: biotin Non-genetic confirmatory testing: biotinidase enzyme activity in serum or plasma |
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| BabyScreen+ newborn screening v0.268 | CYP21A2 | Zornitza Stark reviewed gene: CYP21A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, 201910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.245 | LRPPRC | Zornitza Stark Phenotypes for gene: LRPPRC were changed from Leigh syndrome to Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.243 | LRPPRC | Zornitza Stark reviewed gene: LRPPRC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.229 | MAFB | David Amor reviewed gene: MAFB: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: Multicentric carpotarsal osteolysis syndrome, renal failure; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.222 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. |
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| BabyScreen+ newborn screening v0.191 | ATP6V1B1 | Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from Renal tubular acidosis & hearing loss, MIM#267300 to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.190 | ATP8B1 | Zornitza Stark Phenotypes for gene: ATP8B1 were changed from Cholestasis, progressive familial intrahepatic 1 to Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Cholestasis, benign recurrent intrahepatic, MIM# 243300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.188 | ATP8B1 | Zornitza Stark reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, progressive familial intrahepatic 1, MIM# 211600, Cholestasis, benign recurrent intrahepatic, MIM# 243300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.188 | ACVRL1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available.; to: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available. However, management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.138 | ATP6V1B1 | Zornitza Stark reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.138 | ATP6V0A4 | Zornitza Stark reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular acidosis, distal, autosomal recessive, MIM#602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.125 | ARPC1B |
Zornitza Stark changed review comment from: Established gene-disease association, 3 families and functional data. Severe disorder with onset in infancy/childhood. Recurrent infections and inflammatory features such as vasculitis and eczema. Treatable: bone marrow transplant.; to: Established gene-disease association, 9 families and functional data. Severe disorder with onset in infancy/childhood. Recurrent infections and inflammatory features such as vasculitis and eczema. Treatable: bone marrow transplant. |
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| BabyScreen+ newborn screening v0.83 | AMN |
Zornitza Stark changed review comment from: Well established gene-disease association. Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anaemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood.; to: Well established gene-disease association. Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anaemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Clinical features include failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Treatment: cobalamin. |
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| BabyScreen+ newborn screening v0.57 | ABCD1 | Zornitza Stark Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy to Adrenoleukodystrophy, MIM# 300100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.56 | ABCD1 | Zornitza Stark reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenoleukodystrophy, MIM# 300100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.51 | ABCB11 | Zornitza Stark Phenotypes for gene: ABCB11 were changed from Cholestasis, progressive familial intrahepatic 2 to Cholestasis, progressive familial intrahepatic 2, MIM# 601847; Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.49 | ABCB11 | Zornitza Stark reviewed gene: ABCB11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, progressive familial intrahepatic 2, MIM# 601847, Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.35 | ALDH3A2 | Zornitza Stark Phenotypes for gene: ALDH3A2 were changed from Sjogren-Larsson syndrome to Sjogren-Larsson syndrome MIM#270200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.33 | ALDH3A2 | Zornitza Stark reviewed gene: ALDH3A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sjogren-Larsson syndrome MIM#270200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.3 | ACE | Zornitza Stark Phenotypes for gene: ACE were changed from Renal tubular dysgenesis to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.0 | ACE | Zornitza Stark reviewed gene: ACE: Rating: RED; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.0 | SLC4A4 |
Zornitza Stark gene: SLC4A4 was added gene: SLC4A4 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: SLC4A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC4A4 were set to Renal tubular acidosis, proximal, with ocular abnormalities |
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| BabyScreen+ newborn screening v0.0 | SLC16A12 |
Zornitza Stark gene: SLC16A12 was added gene: SLC16A12 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: SLC16A12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SLC16A12 were set to Cataract, juvenile with microcornea and renal glucosuria |
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| BabyScreen+ newborn screening v0.0 | SIX5 |
Zornitza Stark gene: SIX5 was added gene: SIX5 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: SIX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SIX5 were set to Branchiootorenal syndrome |
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| BabyScreen+ newborn screening v0.0 | SIX2 |
Zornitza Stark gene: SIX2 was added gene: SIX2 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: SIX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SIX2 were set to Renal hypodysplasia |
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| BabyScreen+ newborn screening v0.0 | PDE11A |
Zornitza Stark gene: PDE11A was added gene: PDE11A was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: PDE11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PDE11A were set to Adrenocortical hyperplasia |
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| BabyScreen+ newborn screening v0.0 | HNF1B |
Zornitza Stark gene: HNF1B was added gene: HNF1B was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: HNF1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: HNF1B were set to Renal cysts and diabetes syndrome |
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| BabyScreen+ newborn screening v0.0 | AGTR1 |
Zornitza Stark gene: AGTR1 was added gene: AGTR1 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AGTR1 were set to Renal tubular dysgenesis |
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| BabyScreen+ newborn screening v0.0 | AGT |
Zornitza Stark gene: AGT was added gene: AGT was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AGT were set to Renal tubular dysgenesis |
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| BabyScreen+ newborn screening v0.0 | ACTB |
Zornitza Stark gene: ACTB was added gene: ACTB was added to gNBS. Sources: Expert Review Red,BabySeq Category A gene,BabySeq Category C gene Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ACTB were set to Baraitser-Winter syndrome; Neutrophil dysfunction and recurrent infection |
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| BabyScreen+ newborn screening v0.0 | VPS33B |
Zornitza Stark gene: VPS33B was added gene: VPS33B was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: VPS33B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VPS33B were set to Arthrogryposis renal dysfunction cholestasis syndrome |
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| BabyScreen+ newborn screening v0.0 | VIPAS39 |
Zornitza Stark gene: VIPAS39 was added gene: VIPAS39 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction and cholestasis |
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| BabyScreen+ newborn screening v0.0 | TBX19 |
Zornitza Stark gene: TBX19 was added gene: TBX19 was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: TBX19 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBX19 were set to Adrenocorticotropic hormone deficiency, MIM#201400 |
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| BabyScreen+ newborn screening v0.0 | STAT3 |
Zornitza Stark gene: STAT3 was added gene: STAT3 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: STAT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: STAT3 were set to Hyper-IgE recurrent infection syndrome |
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| BabyScreen+ newborn screening v0.0 | STAR |
Zornitza Stark gene: STAR was added gene: STAR was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STAR were set to Congenital lipoid adrenal hyperplasia, MIM#201710 |
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| BabyScreen+ newborn screening v0.0 | SLC5A2 |
Zornitza Stark gene: SLC5A2 was added gene: SLC5A2 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: SLC5A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC5A2 were set to Renal glucosuria |
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| BabyScreen+ newborn screening v0.0 | SIX1 |
Zornitza Stark gene: SIX1 was added gene: SIX1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: SIX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SIX1 were set to Branchiootorenal syndrome |
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| BabyScreen+ newborn screening v0.0 | SIL1 |
Zornitza Stark gene: SIL1 was added gene: SIL1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: SIL1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SIL1 were set to Marinesco-Sjogren syndrome |
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| BabyScreen+ newborn screening v0.0 | REN |
Zornitza Stark gene: REN was added gene: REN was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: REN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: REN were set to Renal tubular dysgenesis |
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| BabyScreen+ newborn screening v0.0 | OCRL |
Zornitza Stark gene: OCRL was added gene: OCRL was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: OCRL was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: OCRL were set to Lowe oculocerebrorenal syndrome |
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| BabyScreen+ newborn screening v0.0 | NR0B1 |
Zornitza Stark gene: NR0B1 was added gene: NR0B1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: NR0B1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: NR0B1 were set to Congenital adrenal hypoplasia |
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| BabyScreen+ newborn screening v0.0 | NEK8 |
Zornitza Stark gene: NEK8 was added gene: NEK8 was added to gNBS. Sources: Expert Review Green,BabySeq Category C gene Mode of inheritance for gene: NEK8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEK8 were set to 26967905; 33131162; 26697755; 23274954; 26862157; 31633649; 23418306 Phenotypes for gene: NEK8 were set to MONDO:0014174; Renal-hepatic-pancreatic dysplasia 2, MIM# 615415 |
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| BabyScreen+ newborn screening v0.0 | HSD3B2 |
Zornitza Stark gene: HSD3B2 was added gene: HSD3B2 was added to gNBS. Sources: Expert list,BeginNGS,Expert Review Green Mode of inheritance for gene: HSD3B2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HSD3B2 were set to Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency MIM# 201810 |
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| BabyScreen+ newborn screening v0.0 | HNF4A |
Zornitza Stark gene: HNF4A was added gene: HNF4A was added to gNBS. Sources: BeginNGS,Expert Review Green,BabySeq Category C gene Mode of inheritance for gene: HNF4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: HNF4A were set to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850 |
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| BabyScreen+ newborn screening v0.0 | GATA3 |
Zornitza Stark gene: GATA3 was added gene: GATA3 was added to gNBS. Sources: Expert list,Expert Review Green Mode of inheritance for gene: GATA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: GATA3 were set to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255 |
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| BabyScreen+ newborn screening v0.0 | FOXI1 |
Zornitza Stark gene: FOXI1 was added gene: FOXI1 was added to gNBS. Sources: Expert list,Expert Review Green Mode of inheritance for gene: FOXI1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FOXI1 were set to sensorineural deafness and distal renal tubular acidosis |
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| BabyScreen+ newborn screening v0.0 | FAM58A |
Zornitza Stark gene: FAM58A was added gene: FAM58A was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: FAM58A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: FAM58A were set to Syndactyly - telecanthus - anogenital and renal malformations |
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| BabyScreen+ newborn screening v0.0 | EYA1 |
Zornitza Stark gene: EYA1 was added gene: EYA1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: EYA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: EYA1 were set to Branchiootorenal syndrome |
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| BabyScreen+ newborn screening v0.0 | CYP21A2 |
Zornitza Stark gene: CYP21A2 was added gene: CYP21A2 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: CYP21A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP21A2 were set to Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, MIM#201910 |
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| BabyScreen+ newborn screening v0.0 | CYP11B1 |
Zornitza Stark gene: CYP11B1 was added gene: CYP11B1 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: CYP11B1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP11B1 were set to Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, MIM#202010 |
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| BabyScreen+ newborn screening v0.0 | CYP11A1 |
Zornitza Stark gene: CYP11A1 was added gene: CYP11A1 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: CYP11A1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP11A1 were set to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM#613743 |
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| BabyScreen+ newborn screening v0.0 | CLDN19 |
Zornitza Stark gene: CLDN19 was added gene: CLDN19 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: CLDN19 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CLDN19 were set to Hypomagnesemia 5, renal, with ocular involvement |
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| BabyScreen+ newborn screening v0.0 | CA2 |
Zornitza Stark gene: CA2 was added gene: CA2 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis |
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| BabyScreen+ newborn screening v0.0 | ATP6V1B1 |
Zornitza Stark gene: ATP6V1B1 was added gene: ATP6V1B1 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ATP6V1B1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP6V1B1 were set to Renal tubular acidosis & hearing loss, MIM#267300 |
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| BabyScreen+ newborn screening v0.0 | ATP6V0A4 |
Zornitza Stark gene: ATP6V0A4 was added gene: ATP6V0A4 was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: ATP6V0A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP6V0A4 were set to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, MIM3 602722 |
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| BabyScreen+ newborn screening v0.0 | ALDH3A2 |
Zornitza Stark gene: ALDH3A2 was added gene: ALDH3A2 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome |
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| BabyScreen+ newborn screening v0.0 | ACE |
Zornitza Stark gene: ACE was added gene: ACE was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACE were set to Renal tubular dysgenesis |
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| BabyScreen+ newborn screening v0.0 | ABCD1 |
Zornitza Stark gene: ABCD1 was added gene: ABCD1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ABCD1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: ABCD1 were set to Adrenoleukodystrophy |
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