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| Mendeliome v1.1802 | ICOSLG | Zornitza Stark Phenotypes for gene: ICOSLG were changed from Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia to Immunodeficiency 119, MIM# 620825; Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1801 | ICOSLG | Zornitza Stark edited their review of gene: ICOSLG: Changed phenotypes: Immunodeficiency 119, MIM# 620825, Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1510 | RHOXF1 |
Chris Ciotta gene: RHOXF1 was added gene: RHOXF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RHOXF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: RHOXF1 were set to PMID: 38258527 Phenotypes for gene: RHOXF1 were set to Spermatogenic failure, MONDO:0004983, RHOXF1-related Review for gene: RHOXF1 was set to AMBER Added comment: In a cohort of 1,201 men from China with oligozoospermia and azoospermia, hemizygous RHOXF1 variants were identified in 4 unrelated individuals. Three of these variants were missense variants (V130M, A91V & A156V), all were absent from gnomAD (including version 4) and had deleterious in silicos. The one other variant was a nonsense variant (R160X) which is predicted to escape NMD and truncate the protein. This is seen in gnomAD version 4 in 1 heterozygote female, and absent in other versions. In vitro functional evidence for these variants was provided, the V130M, A156V and R160X mutants demonstrated impaired protein localisation with an increase in the protein in the cytoplasm and impaired nuclear entry, the A91V mutant protein did not share these localisation defects. Further, The V130M mutant protein decreased DMRT1 promotor activity, DMRT1 is considered essential for testicular development and spermatogenesis. However, the R160X variant demonstrated increased activation, three times higher than WT. The two other missense variants had no effect. Sources: Literature |
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| Mendeliome v1.1401 | PPID |
Elena Savva gene: PPID was added gene: PPID was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPID was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PPID were set to 37977818 Phenotypes for gene: PPID were set to Stutter disorder, (MONDO:0000723), PPID-related Review for gene: PPID was set to RED Added comment: PMID: 37977818 - a large family (10 affected confirmed to have the variant) with stuttering/language disorder and a het missense (p.(Pro270Ser)). Mouse K/I model showed microstructural changes in the corticospinal tract Sources: Literature |
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| Mendeliome v1.1156 | APOO |
Zornitza Stark edited their review of gene: APOO: Added comment: PMID: 37649161 1 family, 2 individuals (male & female) with same NMD variant c.532G>T (p.E178*), maternally inherited (mother unaffected). Both died before 18 months of age with partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. Other phenotypes included partial syndactyly of the 2nd and 3rd toes, wrinkled palm, and sole skin. Functional studies included site directed mutagenesis. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells.; Changed publications: 37649161; Changed phenotypes: Mitochondrial disease, MONDO:0044970, APOO-related, Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour |
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| Mendeliome v1.958 | DCAF13 |
Michelle Torres gene: DCAF13 was added gene: DCAF13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DCAF13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DCAF13 were set to 36797467 Phenotypes for gene: DCAF13 were set to Neuromuscular disease (MONDO#0019056), DCAF13-related Review for gene: DCAF13 was set to RED Added comment: One consanguineous family, 4x individuals homozygous NM_015420.7(DCAF13)c.907 G > A; p.(Asp303Asn) (3x via WES and 1x via Sanger) with a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy. In silicos analysis of mutant DCAF13 suggests that the amino acid change is deleterious and affects a ß-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Functional studies were not performed. Previously, a heterozygous variant in DCAF13 with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder. Sources: Literature |
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| Mendeliome v1.211 | BMP3 |
Seb Lunke gene: BMP3 was added gene: BMP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP3 were set to 35089417 Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129 Review for gene: BMP3 was set to AMBER Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive Sources: Literature |
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| Mendeliome v0.12230 | SERPINA6 | Zornitza Stark Phenotypes for gene: SERPINA6 were changed from to Corticosteroid-binding globulin deficiency, MIM#611489; Corticosteroid-binding globulin deficiency, MONDO#0012675 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12224 | SERPINA6 | Samantha Ayres reviewed gene: SERPINA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11502797, 27214312, 21795453, 34308089, 22013108; Phenotypes: Corticosteroid-binding globulin deficiency, MIM#611489, Corticosteroid-binding globulin deficiency, MONDO#0012675; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11408 | ICOS | Zornitza Stark Marked gene: ICOS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11408 | ICOS | Zornitza Stark Gene: icos has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11408 | ICOS | Zornitza Stark Phenotypes for gene: ICOS were changed from to Immunodeficiency, common variable, 1 MIM# 607594 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11407 | ICOS | Zornitza Stark Publications for gene: ICOS were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11406 | ICOS | Zornitza Stark Mode of inheritance for gene: ICOS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11405 | ICOS | Zornitza Stark reviewed gene: ICOS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12577056, 15507387, 19380800, 28861081, 31858365, 11343122, 16982935; Phenotypes: Immunodeficiency, common variable, 1 MIM# 607594; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10953 | FUZ |
Ain Roesley gene: FUZ was added gene: FUZ was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FUZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FUZ were set to 21840926 Phenotypes for gene: FUZ were set to {Neural tube defects, susceptibility to} MIM#182940 Penetrance for gene: FUZ were set to unknown Review for gene: FUZ was set to RED gene: FUZ was marked as current diagnostic Added comment: Spina bifida cohort. Negative for VANGL1 and VANGL2, only FUZ was sequenced. Variants identified in 5 individuals. Arg404Gln (39 hets in gnomAD) and Asp354Tyr (6 hets in gnomAD). These variants are listed as risk factor in ClinVar Pro39Ser (absent in gnomAD) was de novo by parental sanger and showed reduced cell mobility on scratch assays. 2 other variants Gly140Glu and Ser142Thr were deemed non-causative due to poor in silicos and conservation Finally, hom KO mouse models were done to prove neural tube defects Sources: Literature |
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| Mendeliome v0.9328 | UNC13B |
Zornitza Stark gene: UNC13B was added gene: UNC13B was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: UNC13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: UNC13B were set to 33876820 Phenotypes for gene: UNC13B were set to Epilepsy Review for gene: UNC13B was set to RED Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex). Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Conflicting data esp regarding MOI, and evidence for pathogenicity of several of the variants is limited. Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified: x1 de novo nonsense variant, absent in gnomad, damaging in silicos x1 de novo splice site, absent in gnomad, damaging in silicos x1 splice site variant present in unaffected mother (low frequency in gnomad) x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad) x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad x1 missense variant - highly conserved residue, not in gnomad x2 other missense variant - highly conserved residue, low frequency in gnomad Latter 4 missense variants cosegregated with affected individuals in the families In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder Sources: Expert Review |
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| Mendeliome v0.7113 | MESP1 |
Zornitza Stark gene: MESP1 was added gene: MESP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203 Phenotypes for gene: MESP1 were set to Congenital heart disease Review for gene: MESP1 was set to AMBER Added comment: Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development. Sources: Expert list |
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| Mendeliome v0.7084 | FBN2 |
Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy. Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.6526 | APOO |
Arina Puzriakova gene: APOO was added gene: APOO was added to Mendeliome. Sources: Literature Mode of inheritance for gene: APOO was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: APOO were set to 32439808 Phenotypes for gene: APOO were set to Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour Review for gene: APOO was set to RED Added comment: - PMID: 32439808 (2021) - Three generation family with c.350T>C variant in APOO, encoding a component of the MICOS complex which plays a role in maintaining inner mitochondrial membrane architecture. Phenotypes include fatigue and muscle weakness (6/8), learning difficulties and cognitive impairment (4/8), and increased blood lactate (2/8). Four individuals were asymptomatic carriers, including one male (authors indicate variability in female carriers was due to skewed X-inactivation, although skewing studies were inconclusive in some cases). Variability in clinical presentation suggests reduced penetrance or possible contribution of additional factors. Functional studies showed altered MICOS assembly and abnormalities in mitochondria ultrastructure in patient-derived fibroblasts. Knockdown studies in Drosophila and yeast demonstrated mitochondrial structural and functional deficiencies. Sources: Literature |
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| Mendeliome v0.6485 | MAST2 |
Elena Savva gene: MAST2 was added gene: MAST2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAST2 were set to PMID: 33465109 Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis Review for gene: MAST2 was set to RED Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression. RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets Sources: Literature |
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| Mendeliome v0.2573 | NKX2-3 |
Zornitza Stark gene: NKX2-3 was added gene: NKX2-3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NKX2-3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NKX2-3 were set to 31498527 Phenotypes for gene: NKX2-3 were set to Intestinal varicosities Review for gene: NKX2-3 was set to RED Added comment: Single multiplex family where truncating variant in this gene segregated with intestinal varicosities with a LOD score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Sources: Literature |
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| Mendeliome v0.2020 | ICOSLG | Zornitza Stark Marked gene: ICOSLG as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2020 | ICOSLG | Zornitza Stark Gene: icoslg has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2020 | ICOSLG | Zornitza Stark Phenotypes for gene: ICOSLG were changed from to Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2019 | ICOSLG | Zornitza Stark Publications for gene: ICOSLG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2018 | ICOSLG | Zornitza Stark Mode of inheritance for gene: ICOSLG was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2017 | ICOSLG | Zornitza Stark Classified gene: ICOSLG as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2017 | ICOSLG | Zornitza Stark Gene: icoslg has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2016 | ICOSLG | Zornitza Stark reviewed gene: ICOSLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 31532372, 30498080; Phenotypes: Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.671 | C19orf70 |
Zornitza Stark gene: C19orf70 was added gene: C19orf70 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: C19orf70 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C19orf70 were set to 29618761; 27623147; 27485409 Phenotypes for gene: C19orf70 were set to Combined oxidative phosphorylation deficiency 37, MIM# 618329 Review for gene: C19orf70 was set to GREEN Added comment: Three unrelated families reported. HGNC approved name MICOS13. Sources: Expert list |
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| Mendeliome v0.0 | ICOSLG |
Zornitza Stark gene: ICOSLG was added gene: ICOSLG was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ICOSLG was set to Unknown |
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| Mendeliome v0.0 | ICOS |
Zornitza Stark gene: ICOS was added gene: ICOS was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ICOS was set to Unknown |
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