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| Muscular dystrophy and myopathy_Paediatric v1.29 | COMP | Ain Roesley Marked gene: COMP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.29 | COMP | Ain Roesley Gene: comp has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.29 | COMP | Ain Roesley Classified gene: COMP as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.29 | COMP | Ain Roesley Gene: comp has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.28 | COMP |
Ain Roesley gene: COMP was added gene: COMP was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: COMP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: COMP were set to 20508815; 14684695; 15880723 Phenotypes for gene: COMP were set to Epiphyseal dysplasia, multiple, 1 MIM#132400 Review for gene: COMP was set to AMBER gene: COMP was marked as current diagnostic Added comment: Not a common feature of MED. Amber so as not to miss a diagnosis PMID: 14684695 2 families only 1 with mild myopathy Fam1: 1 father + 3 sibs, only 1 reported muscle weakness Fam2: no muscle weakness reported PMID: 15880723 10 families but only 1 reported mild myopathy PMID: 20508815 additional 2 unrelated individuals from European Skeletal Dysplasia Network Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v1.13 | CIAO1 |
Paul De Fazio gene: CIAO1 was added gene: CIAO1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CIAO1 were set to 38411040; 38196629 Phenotypes for gene: CIAO1 were set to Neuromuscular disease, CIAO1-related (MONDO:0019056) Penetrance for gene: CIAO1 were set to unknown Review for gene: CIAO1 was set to GREEN gene: CIAO1 was marked as current diagnostic Added comment: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. Muscle biopsy showed variation in fiber size and an increase in internalized nuclei, as well as scattered degenerating/regenerating fibers and a mild to minimal increase in endomysial fibrosis. Electron microscopy revealed morphologically abnormal mitochondria. PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out. All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v1.11 | TUBA4A |
Sarah Pantaleo gene: TUBA4A was added gene: TUBA4A was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TUBA4A were set to PMID: 38413182 Phenotypes for gene: TUBA4A were set to Congenital myopathy MONDO:0019952 Review for gene: TUBA4A was set to AMBER Added comment: One novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. Identified candidate genes using laser capture micro dissection, proteomics, WES, clinical data, myopathological changes, electrophysiological exams and thigh muscle MRIs. The variant is de novo in both patients, c.679C>T, p.(Leu227Phe). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiqution-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of Leu227Phe resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model. Patient 1 is 14yo and had delayed motor development milestones since infancy. Myopathic face, high-arched palate, waddling gait, winged scapula and muscle weakness in four limbs with lower extremities and proximal muscle more severely affected. Follow up at 14yo showed slight improvement in motor function compared with 3yo. Patient 2 is 6yo and presented with motor retardation since birth. At 3yo, presented with mild ptosis and ophthalmoparesis, high-arched palate and muscle weakness involving both proximal and distal in all limbs. No likely pathogenic variants in 116 other protein-encoding genes. Variants confirmed by Sanger sequencing and absent from gnomAD. ACMG predicts likely pathogenic classification. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v0.128 | TPM3 |
Sangavi Sivagnanasundram gene: TPM3 was added gene: TPM3 was added to Muscular dystrophy_Paediatric. Sources: Other Mode of inheritance for gene: TPM3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TPM3 were set to 26418456; 18300303; 10619715; 12196661; 18382475 Phenotypes for gene: TPM3 were set to Congenital myopathy 4A, autosomal dominant (MIM#255310); Congenital myopathy 4B, autosomal recessive (MIM#609284) Review for gene: TPM3 was set to GREEN Added comment: Variable age of onset due to the variability of phenotypes. Mutations in TPM3 cause a diverse group of congenital myopathies all characterised by muscle weakness/hypotonia. AD Congenital Myopathy: PMID: 26418456 Quantitative in vitro motility assay show that gain of function is mechanism of disease - mutations in the TPM3 gene led to an increased function in the myofibres/muscle cells. 2 unrelated individuals with ΔE218 and ΔE224 de novo deletions in TPM3 with muscle stiffness. Both muscle biopsies showed features of mild myopathy. PMID: 18300303 4 individuals with phenotypic features of congenital myopathy and mutation present in TPM3 AR Congenital myopathy: PMID: 10619715 Individual from consanguineous parents with severe symptoms of congenital myopathy PMID: 12196661 Individual who is a compound heterozygote for nemaline myopathy PMID: 18382475 Affected individuals from two turkish families with myopathy phenotypes. Sources: Other |
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| Muscular dystrophy and myopathy_Paediatric v0.128 | LMOD3 |
Sangavi Sivagnanasundram gene: LMOD3 was added gene: LMOD3 was added to Muscular dystrophy_Paediatric. Sources: Other Mode of inheritance for gene: LMOD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LMOD3 were set to 25250574; 28815944; 30291184 Phenotypes for gene: LMOD3 were set to Nemaline myopathy 10 (MIM# 616165; MONDO:0014513) Review for gene: LMOD3 was set to GREEN Added comment: Age of onset is typically during pregnancy (antenatal) however severity of the condition is variable. Typical phenotypes include: severe generalized hypotonia and weakness at birth, respiratory insufficiency, feeding difficulties, and bulbar weakness PMID: 25250574 Multiple individuals from unrelated families (21 individuals from 14 patients). Segregation analysis was consistent of an AR inheritance Zebrafish model showed the complete loss of function in myotubes resulting in abnormal motor function. Sources: Other |
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| Muscular dystrophy and myopathy_Paediatric v0.128 | CNTN1 |
Sangavi Sivagnanasundram gene: CNTN1 was added gene: CNTN1 was added to Muscular dystrophy_Paediatric. Sources: Other Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CNTN1 were set to 10926398 Phenotypes for gene: CNTN1 were set to Congenital Myopathy 12, Compton-North myopathy (MONDO:0012929; MIM#612540) Review for gene: CNTN1 was set to AMBER Added comment: PMID: 10926398 single family reported with clinical features consistent with severe lethal myopathy (age of onset is unknown as only one family has been reported) Sources: Other |
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| Muscular dystrophy and myopathy_Paediatric v0.128 | BIN1 |
Sangavi Sivagnanasundram gene: BIN1 was added gene: BIN1 was added to Muscular dystrophy_Paediatric. Sources: Other Mode of inheritance for gene: BIN1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: BIN1 were set to 17676042; 29950440 Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2 (MONDO: 0009709; MIM#255200) Review for gene: BIN1 was set to GREEN Added comment: PMID: 17676042 3 unrelated consanguineous families with centronuclear myopathy 2. Age of onset ranged from birth to childhood PMID: 29950440 Homozygous patients have a more specific and severe phenotype compared to compound heterozygous patients with similar age of onset Sources: Other |
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| Muscular dystrophy and myopathy_Paediatric v0.121 | POGLUT1 |
Zornitza Stark gene: POGLUT1 was added gene: POGLUT1 was added to Muscular dystrophy_Paediatric. Sources: Literature Mode of inheritance for gene: POGLUT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POGLUT1 were set to 33861953 Phenotypes for gene: POGLUT1 were set to Muscular dystrophy, MONDO:0020121, POGLUT1-related Review for gene: POGLUT1 was set to AMBER Added comment: in addition to adult-onset LGMD R21 (OMIM# 617232), biallelic variants in POGLUT1 gene have been reported in one patient with congenital muscular dystrophy and in two further patients with onset before 3 years of age. The presenting symptom were hypotonia with lower limb proximal weakness after gait acquisition, and further progression with mild weakness, wasting and contractures of the upper limbs, mild facial weakness, ptosis, and nasal voice. weakness was more severe and had faster progression compared to later onset patients. Muscle biopsies show evidence of α-dystroglycan hypoglycosylation. POGLUT1 activity is critical for the Notch signalling pathway, as JAG2. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v0.88 | JAG2 |
Zornitza Stark gene: JAG2 was added gene: JAG2 was added to Muscular dystrophy_Paediatric. Sources: Literature Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: JAG2 were set to 33861953 Phenotypes for gene: JAG2 were set to muscular dystrophy Review for gene: JAG2 was set to GREEN Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v0.15 | COL4A2 |
Elena Savva gene: COL4A2 was added gene: COL4A2 was added to Muscular dystrophy. Sources: Expert list Mode of inheritance for gene: COL4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COL4A2 were set to PMID: 25719457; 30315939 Phenotypes for gene: COL4A2 were set to Brain small vessel disease 2 614483 Penetrance for gene: COL4A2 were set to Incomplete Mode of pathogenicity for gene: COL4A2 was set to Other Review for gene: COL4A2 was set to RED Added comment: OMIM reports - Variable severity - Incomplete penetrance PMID: 25719457 - 0/15 heterozygous carriers report any myopathy phenotype. Majority had porencephaly or periventricular leukoencephalopathy. PMID: 30315939 - two patients with schizencephaly and/or polymicrogyria. Authors specifically noted myopathy was not observed in any patient, one was reported to have normal CK levels. Both LOF and dominant negative are suggested mechanisms for this gene. Sources: Expert list |
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