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| Congenital myopathy v7.75 | TNPO3 |
Achchuthan Shanmugasundram changed review comment from: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age. PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro). PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant. PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).; to: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age. PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro). PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant. It appears that PMID:31217819 describes the same Hungarian family form the descriptions. PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206). |
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| Congenital myopathy v7.70 | MCOLN1 |
Eleanor Williams changed review comment from: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248) PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant. The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap Other publications that mention a myopathy phenotype in ML4 patients: PMID: 32604955 Jezela-Stanek et al 2020 Report 2 Pakistani patients with adult onset myopathy both with homozygous MCOLN1 c.[1256G>C];p.(Arg419Pro), elevated creatine kinase and myopathy (no biopsy).; to: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248) 1 case ( Zambon et al 2021) reported of a young child with ML4 and elevated creatine kinase, a myopathy confirmed by electromyography and a homogyzous truncating variant in MCOLN1. 2 other cases with elevated creatine kinase reported. PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant. The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap Other publications that mention a myopathy phenotype in ML4 patients: PMID:32604955 Jezela-Stanek et al 2020 Report 2 Pakistani patients both with homozygous MCOLN1 c.[1256G>C];p.(Arg419Pro), elevated creatine kinase and myopathy (no biopsy reported) as part of their clinical features. One with congenital myopathy, other with no age of onset given but text suggests adult onset. Unclear if related or not. PMID:42037965 Alsahlawi et al 2026 10-year-old boy from Bahrain with ML4 who presented with global developmental delay, spastic quadriparesis, severe visual impairment, gastrointestinal manifestations, and persistent elevation of creatine kinase (CK) suggestive of potential secondary myopathic involvement. No muscle biopsy reported. CK level first measured above normal at 1 year 3 months. WES identified a homozygous MCOLN1 variant (c.1336G>A; p.Val446Met). Parents were both heterozygous. |
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| Congenital myopathy v7.36 | CNTN1 |
Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. The siblings died after 3 and 5 days after birth. This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026). |
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| Congenital myopathy v7.34 | CNTN1 |
Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026). |
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| Congenital myopathy v7.34 | CNTN1 |
Achchuthan Shanmugasundram commented on gene: CNTN1: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026). |
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| Congenital myopathy v5.4 | MYMX |
Dmitrijs Rots gene: MYMX was added gene: MYMX was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene: MYMX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYMX were set to PMID: 39668186 Phenotypes for gene: MYMX were set to congenital myopathy with recognizable facial palsy, growth restriction, and dysmorphism Penetrance for gene: MYMX were set to Complete Review for gene: MYMX was set to GREEN Added comment: The PMID: 39668186 describes additional 2 (to previous 2; total 4) patients with congenital myopathy with recognizable facial palsy, growth restriction, and dysmorphism. Enough evidence for the green rating. Probably the gene should be added also to the short stature panel? Sources: Literature |
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||