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| Congenital myopathy v4.35 | VWA1 |
Eleanor Williams gene: VWA1 was added gene: VWA1 was added to Congenital myopathy. Sources: Literature Q1_24_promote_green, Q1_24_expert_review tags were added to gene: VWA1. Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA1 were set to 33459760 Phenotypes for gene: VWA1 were set to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977 Added comment: In PMID: 33459760 Deschauer et al 2021 report 15 affected individuals from six families of German, Arabic, and Roma descent with biallelic loss of function variants in VWA1 and a neuromuscular phenotype. In 3 of the families the onset of symptoms was in childhood (ages 2-18yr in F3, ages 2-3yr in F4, and at school age in F5). Muscle biopsies of 3 individuals (F1-II.2, F2-II.1, and F5-II.1) revealed myopathic changes. A 10-bp tandem repeat is duplicated in one variant (p.Gly25Argfs*74]) and deleted in another variant (p.Gly21Alafs*12]). The duplication was found in 3 German families, homozygous in one and compound heterozygous in the other two. PMID: 33559681 Pagnamenta et al 2021 report 17 individuals from 15 families with an autosomal-recessive, hereditary motor neuropathy and rare biallelic variants in VWA1. The p.(G25Rfs*74) 10-bp repeat expansion was observed in 14/15 families and was homozygous in 10/15. The authors state that the mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations. Given the young age of onset in some patients and myopathy seen in biopsys this gene may be a candidate for green rating on this panel, subject to expert review. Sources: Literature |
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| Congenital myopathy v4.27 | ZC4H2 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Anna Sarkozy (Great Ormond Street Hospital) and others, variants in ZC4H2 cause a clinical phenotype that includes congenital arthrogryposis, joint contractures and muscle weakness similar to that has been seen in structural myopathies. As there is sufficient number of cases, this gene can be promoted to green at the next major review.; to: Comment on list classification: As reviewed by Anna Sarkozy (Great Ormond Street Hospital) and others, variants in ZC4H2 cause a clinical phenotype that includes congenital arthrogryposis, joint contractures and muscle weakness similar to what has been seen in structural myopathies. As there is sufficient number of cases, this gene can be promoted to green at the next major review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.27 | ZC4H2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy (Great Ormond Street Hospital) and others, variants in ZC4H2 cause a clinical phenotype that includes congenital arthrogryposis, joint contractures and muscle weakness similar to that has been seen in structural myopathies. As there is sufficient number of cases, this gene can be promoted to green at the next major review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.26 | ADSSL1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), evidence from scientific literature show that the onset of distal myopathy caused by ADSSL1 variants is during late childhood/ adolescence in majority of reported cases. Patients with ADSSL1 myopathy typically visit the hospital for muscle weakness during adulthood; however, all the patients have a history of being the slowest runner among their peers during childhood, which is a characteristic feature of ADSSL1 myopathy. Patients with ADSSL1 myopathy develop distal muscle weakness, including significant post-puberty grip weakness, which occurs in all patients (PMID:35668205). However, the review of previously reported patients in PMID:28268051 described patients with early childhood onset, with the youngest patient reported at 5 years of age. PMID:31680123 reported one case identified with homozygous frameshift variant and presented with congenital joint contractures and a more severe neurological phenotype,; to: As reviewed by Zornitza Stark (Australian Genomics), evidence from scientific literature show that the onset of distal myopathy caused by ADSSL1 variants is during late childhood/ adolescence in the reported cases. Patients with ADSSL1 myopathy typically visit the hospital for muscle weakness during adulthood; however, all the patients have a history of being the slowest runner among their peers during childhood, which is a characteristic feature of ADSSL1 myopathy. Patients with ADSSL1 myopathy develop distal muscle weakness, including significant post-puberty grip weakness, which occurs in all patients (PMID:35668205). Patients reported in PMIDs: 26506222 & 28268051 developed diffuse muscle weakness initially around 5-8 years of age, although distal leg weakness started at adolescence (13-17 years of age). PMID:31680123 reported one case identified with homozygous frameshift variant and presented with congenital joint contractures and a more severe neurological phenotype. As the diffuse muscle weakness started at childhood in at least nine cases and there is a case with congenital joint contractures, and this gene was added green as per expert review, we should keep this gene green on this panel. |
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| Congenital myopathy v4.26 | ADSSL1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark (Australian Genomics), evidence from scientific literature show that the onset of distal myopathy caused by ADSSL1 variants is during late childhood/ adolescence in majority of reported cases. Patients with ADSSL1 myopathy typically visit the hospital for muscle weakness during adulthood; however, all the patients have a history of being the slowest runner among their peers during childhood, which is a characteristic feature of ADSSL1 myopathy. Patients with ADSSL1 myopathy develop distal muscle weakness, including significant post-puberty grip weakness, which occurs in all patients. However, the review of previously reported patients in PMID:28268051 described patients with early childhood onset, with the youngest patient reported at 5 years of age. PMID:31680123 reported one case identified with homozygous frameshift variant and presented with congenital joint contractures and a more severe neurological phenotype,; to: As reviewed by Zornitza Stark (Australian Genomics), evidence from scientific literature show that the onset of distal myopathy caused by ADSSL1 variants is during late childhood/ adolescence in majority of reported cases. Patients with ADSSL1 myopathy typically visit the hospital for muscle weakness during adulthood; however, all the patients have a history of being the slowest runner among their peers during childhood, which is a characteristic feature of ADSSL1 myopathy. Patients with ADSSL1 myopathy develop distal muscle weakness, including significant post-puberty grip weakness, which occurs in all patients (PMID:35668205). However, the review of previously reported patients in PMID:28268051 described patients with early childhood onset, with the youngest patient reported at 5 years of age. PMID:31680123 reported one case identified with homozygous frameshift variant and presented with congenital joint contractures and a more severe neurological phenotype, |
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| Congenital myopathy v4.2 | DNAJB4 |
Anna Sarkozy gene: DNAJB4 was added gene: DNAJB4 was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene: DNAJB4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJB4 were set to PMID: 36264506 Phenotypes for gene: DNAJB4 were set to congenital myopathy with early respiratory failure Penetrance for gene: DNAJB4 were set to unknown Mode of pathogenicity for gene: DNAJB4 was set to Other Review for gene: DNAJB4 was set to GREEN Added comment: biallelic variants in DNAJB4 gene have now been described in three unrelated families, in particular stop gain and missense variants. the phenotype is characterised by axial rigidity and early respiratory failure between the 1st and 4th decade of life. muscle pathology is myopathic with protein inclusions and occasional rimmed vacuoles. Sources: Literature |
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| Congenital myopathy v4.2 | TPM2 | Anna Sarkozy edited their review of gene: TPM2: Added comment: comment re inheritance: recessive TPM2 pathogenic variant has been described in a patient with multiple pterygium syndrome and congenital myopathy. heterozygous carrier parents were unaffected, supporting recessive inheritance of the variant.; Changed publications to: 33558124; Changed phenotypes to: CAP myopathy 2 609285, Nemaline myopathy 4, autosomal dominant 609285, recessively inherited Escobar variant of multiple pterygium syndrome and congenital myopathy; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.2 | NEB | Anna Sarkozy edited their review of gene: NEB: Added comment: comment re inheritance: a large in frame deletion in the NEB gene have now been described in a three-generation family and was shown to cause the production of a smaller mutant nebulin protein. Thus, it was suggested that this novel mutant nebulin protein has a dominant-negative effect.; Changed publications to: 12207937, 30679003; Changed phenotypes to: nemaline myopathy, Nemaline Myopathy, Recessive, Nemaline myopathy 2, autosomal recessive, 256030, Dominantly inherited distal nemaline/cap myopathy; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.2 | MYH3 | Anna Sarkozy edited their review of gene: MYH3: Added comment: Recessive MYH3 variants reported in patients with multiple pterygia and this disease entity is designated as "Contractures, pterygia, and variable skeletal fusions syndrome 1B," in OMIM.; Changed publications to: 18695058, 26578207, 32902138; Changed phenotypes to: Arthrogryposis, distal, type 2A 193700, Arthrogryposis, distal, type 2B 601680, Arthrogryposis, distal, type 8 178110, ontractures, pterygia, and variable skeletal fusions syndrome 1B; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.2 | DNM2 | Anna Sarkozy edited their review of gene: DNM2: Added comment: biallelic DNM2 variants were also described in three consanguineous patients with lethal congenital syndrome caractherised by akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages. muscle biopsy and EMG showed myopathic features. in particular, muscle biopsy of one patient showed small rounded fibers with some centralized nuclei, suggestive of a congenital myopathy whereas biopsy of a 2nd patient showed atrophic fibers without obvious centralization of nuclei.; Changed publications to: 22396310, 23092955; Changed phenotypes to: Myopathy, centronuclear, 160150, Charcot-Marie-Tooth disease, axonal, type 2M, 606482, lethal congenital syndrome; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v4.2 | ASCC1 |
Anna Sarkozy gene: ASCC1 was added gene: ASCC1 was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene: ASCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASCC1 were set to PMID: 35838082; 30327447; 35690317 Phenotypes for gene: ASCC1 were set to prenatal-onset muscle weakness; congenital onset myopathy; arthrogryposis; congenital bone fractures Penetrance for gene: ASCC1 were set to unknown Mode of pathogenicity for gene: ASCC1 was set to Other Review for gene: ASCC1 was set to GREEN Added comment: recessive pathogenic variants in ASCC1 gene have now been described in a number of unrelated individuals presenting with a spectrum of phenotypes ranging from prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures to milder presentations without fractures, in keeping with a diagnosis of congenital myopathy . Sources: Literature |
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| Congenital myopathy v4.2 | COL25A1 |
Anna Sarkozy gene: COL25A1 was added gene: COL25A1 was added to Congenital myopathy. Sources: Expert list,Literature,Expert Review,Research Mode of inheritance for gene: COL25A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COL25A1 were set to PMID: 35077597 Phenotypes for gene: COL25A1 were set to rthrogryposis multiplex congenita with or without ocular congenital cranial dysinnervation disorder Penetrance for gene: COL25A1 were set to unknown Mode of pathogenicity for gene: COL25A1 was set to Other Review for gene: COL25A1 was set to GREEN Added comment: pathogenic recessive variants (missense and splice site) in the COL25A1 gene have now been described in three unrelated families (5 patients in total) presenting with arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder, normal CK and absence of abnormalities on EMG. Given similarities of presentations with other forms of myopathic contractural phenotypes and no/mild progression over time, this condition should be considered in differential for congenital myopathies, thus we would recommend to add this gene as green gene into the R81 panel. Sources: Expert list, Literature, Expert Review, Research |
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| Congenital myopathy v3.64 | MT-TL1 | Arina Puzriakova Phenotypes for gene: MT-TL1 were changed from MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS 540000 to MELAS syndrome, MONDO:0010789 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v3.32 | DES | Arina Puzriakova Phenotypes for gene: DES were changed from Myopathy, myofibrillar, 1, 601419; Scapuloperoneal syndrome, neurogenic, Kaeser type, 181400 to Myopathy, myofibrillar, 1, OMIM:601419; Scapuloperoneal syndrome, neurogenic, Kaeser type, OMIM:181400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v3.10 | KY | Sarah Leigh commented on gene: KY: Associated with Myopathy, myofibrillar, 7 (OMIM: 617114) in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants have been reported in unrelated cases. PMID: 30591934 demostrates segregation of KY c.415C>T (p.R139*) in the affected homozygous members of a consanguineous family, where the parents are heterozygotes and the unaffected sister is homozygous for the wild type allele. PMID 27485408 describes the spontaneously generated murine ortholog of variant Ky with postnatally developing kyphoscoliosis, the authors note the similarities between the patient and mouse muscle fibres. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v2.68 | MLIP |
Zornitza Stark gene: MLIP was added gene: MLIP was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MLIP were set to 34581780 Phenotypes for gene: MLIP were set to MLIP-related myopathy with rhabdomyolysis Review for gene: MLIP was set to GREEN Added comment: PMID: 34581780: 7 individuals with 6 families with truncating (one splice that also resulted in a frameshift variant) biallelic variants (used NM_1281746). In 3 patients patients’ skeletal muscle, these variants were shown to cause reduction overall RNA expression levels of the predominant MLIP isoform. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. Sources: Literature |
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| Congenital myopathy v2.53 | TPM2 | Ivone Leong Added comment: Comment on publications: PMID: 19155175 and 33558124 describe the 2 homozygous cases | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v1.166 | TRIP4 |
Louise Daugherty changed review comment from: Reviewed by Ivone Leong (Genomics England Curator) PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this. There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case? Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; to: Reviewed by Ivone Leong (Genomics England Curator) PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this. There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case? Genomics England clinical team noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off. |
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| Congenital myopathy v1.163 | TRIP4 |
Louise Daugherty edited their review of gene: TRIP4: Added comment: Reviewed by Ivone Leong (Genomics England Curator) PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this. There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case? Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN |
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| Congenital myopathy v1.149 | HACD1 | Anna Sarkozy edited their review of gene: HACD1: Added comment: variants were described in a single family in literature. no further confirmation to date; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy | DES | Anna Sarkozy reviewed DES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy | DES | Helen Brittain marked DES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy | DES | Helen Brittain classified DES as red | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy | DES | Helen Brittain reviewed DES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||