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| Muscular dystrophy and myopathy_Paediatric v1.80 | HMGCS1 |
Zornitza Stark gene: HMGCS1 was added gene: HMGCS1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HMGCS1 were set to 39531736 Phenotypes for gene: HMGCS1 were set to Rigid spine syndrome, MONDO:0019951, HMGCS1-related Review for gene: HMGCS1 was set to GREEN Added comment: Five individuals from four families reported. All individuals presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some; one individual died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. Four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v1.76 | DTNA |
Chirag Patel gene: DTNA was added gene: DTNA was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: DTNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DTNA were set to PMID: 36799992 Phenotypes for gene: DTNA were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis MONDO:0859322 Mode of pathogenicity for gene: DTNA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: DTNA was set to GREEN Added comment: 12 individuals from 4 unrelated families with 2 different monoallelic DTNA variants in exon 18 and affecting the coiled-coil domain of α-dystrobrevin (DTNA). DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype. Clinical features with onset between 1st and 4th decades included: myalgia, muscle cramps associated with physical activity, exercise intolerance, and increased serum CK (11/12). Most patients have mild symptoms, only 3 had mild proximal muscle weakness of the lower limbs, and 1 had episode of rhabdomyolysis @20yrs. Muscle biopsies in 8 individuals showed mild myopathic and/or dystrophic features. The 2 variants (p.Glu529Lys and p.Gln523_Glu529del) were found by targeted exome sequencing and confirmed by Sanger sequencing. They segregated with the disorder in the families and were absent in gnomAD. Immunofluorescent analysis of patient muscle samples showed decreased DTNA immunoreactivity at the sarcolemma, as well as variably reduced immunoreactivity of several other dystrophin-glycoprotein complex (DGC) proteins, suggesting that the DTNA variants resulted in overall destabilization of the DG complex within skeletal muscle. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v1.68 | RFC4 |
Chirag Patel gene: RFC4 was added gene: RFC4 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RFC4 were set to PMID: 39106866 Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder Review for gene: RFC4 was set to GREEN gene: RFC4 was marked as current diagnostic Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9). WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease. The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown. Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression. Sources: Literature |
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| Muscular dystrophy and myopathy_Paediatric v1.66 | CSMD1 |
Krithika Murali gene: CSMD1 was added gene: CSMD1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD1 were set to PMID 38816421 Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038 Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected. Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP. Sources: Literature |
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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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