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Cardiomyopathy_Paediatric v1.308 TAFAZZIN Zornitza Stark Phenotypes for gene: TAFAZZIN were changed from Barth syndrome, 302060; Dilated Cardiomyopathy, X-Linked; Left Ventricular Noncompaction Cardiomyopathy; Neutropenia, muscle weakness, growth retardation; Non-compaction cardiomyopathy; HCM, mixed; Disorders of mitochondrial membrane lipids (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial lipid metabolism; Methylglutaconic aciduria type II, Barth syndrome (Organic acidurias); Barth syndrome to Barth syndrome, MIM# 302060
Cardiomyopathy_Paediatric v1.147 NDUFV2 Richard Lin reviewed gene: NDUFV2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMIDs: 12754703, 19167255, 26008862; Phenotypes: Leigh syndrome, MONDO:0009723, Mitochondrial complex I deficiency, nuclear type 7, MIM: 618229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v1.147 DSC2 Richard Lin changed review comment from: Two studies report 3 unrelated patients with biallelic DSC2 variants and paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507). Reported variants in DSC2 are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalizes at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly; to: Association between heterozygous variants and arrhythmogenic right ventricular dysplasia classified as definitive by ClinGen. Reported cases are adult-onset disease.

Two studies report 3 unrelated patients with biallelic DSC2 variants and paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507), though reported variants are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalises at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly
Cardiomyopathy_Paediatric v1.147 DSC2 Richard Lin changed review comment from: Two studies report 3 unrelated patients with paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507). Reported variants are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalizes at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly; to: Two studies report 3 unrelated patients with biallelic DSC2 variants and paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507). Reported variants in DSC2 are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalizes at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly
Cardiomyopathy_Paediatric v1.147 DSC2 Richard Lin changed review comment from: Two studies report 3 unrelated patients with paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507). Reported variants are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalizes at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly; to: Two studies report 3 unrelated patients with paediatric onset arrhythmogenic (right ventricular) cardiomyopathy (PMIDs: 24793512, 26310507). Reported variants are likely VUS.

PMID: 24793512 - 10 year old F with sudden cardiac arrest and typical/advanced features of ARVC, found to be homozygous for an inframe deletion in DSC2:c.712_714delGAT, p.(Asp238del). 2 male sibs and both parents heterozygous for the same variant, clinically unaffected.
PMID: 26310507 - cohort study which found a homozygous missense variant DSC2: c.536A>G, p.(Asp179Gly) in 5 patients from 4 families, including 2 unrelated paediatric patients aged 14 and 11 with arrhythmogenic cardiomyopathy
PMID: 20197793 - functional study which shown that the DSC2 p.Asp179Gly variant protein correctly colocalizes at the cell membrane with endogenous desmoglein in a transfected desmosome-forming cell line, indicating this variant has no impact on desmosome assembly
Cardiomyopathy_Paediatric v1.147 DSC2 Richard Lin reviewed gene: DSC2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMIDs: 20197793, 24793512, 26310507; Phenotypes: Syndromic disease, MONDO:0002254, familial isolated arrhythmogenic right ventricular dysplasia, MONDO:0016342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v1.147 TSFM Richard Lin reviewed gene: TSFM: Rating: GREEN; Mode of pathogenicity: None; Publications: PMIDs: 35071363, 31451716, 31267352, 27677415, 25037205, 21741925, 17033963; Phenotypes: Mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v1.147 TMEM70 Richard Lin reviewed gene: TMEM70: Rating: GREEN; Mode of pathogenicity: None; Publications: PMIDs: 20335238, 26550569, 27649480, 30899493, 30950220, 31729175, 36751706; Phenotypes: mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, MONDO:0013546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v1.147 MMACHC Richard Lin changed review comment from: Biallelic variants in MMACHC are associated with Cobalamin C deficiency (cblC deficiency), a multisystemic condition.

Cardiomyopathy is described to occur in 10-25% of patients with early onset (below the age of 1 year) MMACHC-associated cblC deficiency in the 2026 Remethylation Disorders guidelines (PMID: 42231716). The predominant cardiomyopathy phenotype is left ventricular non compaction cardiomyopathy (PMIDs: 19767224, 20632110, 23430797, 24599607, 40830795, 42231716). Paediatric onset dilated cardiomyopathy has also been rarely reported (PMID: 19248038, 33562640, 38745823); to: Biallelic variants in MMACHC are associated with Cobalamin C deficiency (cblC deficiency), a multisystemic condition.

Cardiomyopathy is described to occur in 10-25% of patients with early onset (below the age of 1 year) MMACHC-associated cblC deficiency in the 2026 Remethylation Disorders guidelines (PMID: 42231716). The predominant cardiomyopathy phenotype is left ventricular non compaction cardiomyopathy (PMIDs: 19767224, 20632110, 23430797, 24599607, 40830795, 42231716). Paediatric onset dilated cardiomyopathy has also been rarely reported (PMID: 19248038, 33562640, 38745823)
Cardiomyopathy_Paediatric v1.139 IDS Zornitza Stark Marked gene: IDS as ready
Cardiomyopathy_Paediatric v1.139 IDS Zornitza Stark Gene: ids has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v1.139 IDS Zornitza Stark Phenotypes for gene: IDS were changed from MPS II, Hunter disease (Mucopolysaccharidoses); MUCOPOLYSACCHARIDOSIS TYPE 2; Mucopolysaccharidosis Type II; Mucopolysaccharidosis II, 309900 to mucopolysaccharidosis type 2, MONDO:0010674
Cardiomyopathy_Paediatric v1.138 IDS Zornitza Stark Publications for gene: IDS were set to 27604308
Cardiomyopathy_Paediatric v1.137 IDS Zornitza Stark reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35882106, 34193122, 32256517, 27146977; Phenotypes: mucopolysaccharidosis type 2, MONDO:0010674; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cardiomyopathy_Paediatric v1.99 MT-ATP6 Zornitza Stark gene: MT-ATP6 was added
gene: MT-ATP6 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Publications for gene: MT-ATP6 were set to 40367733; 40112238; 39119452; 29101127; 27453250
Phenotypes for gene: MT-ATP6 were set to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP6-related
Review for gene: MT-ATP6 was set to GREEN
Added comment: PMIDs 40367733, 29101127, 39119452, 40112238 and 27453250 collectively report 43 families with MT‑ATP6 variants causing mitochondrial disease phenotypes that include cardiomyopathy. 19 families present with Leigh syndrome and hypertrophic cardiomyopathy and 23 families with mitochondrial proton‑transporting ATP synthase complex deficiency and paediatric cardiomyopathy.
Sources: Literature
Cardiomyopathy_Paediatric v1.62 POPDC2 Rylee Peters gene: POPDC2 was added
gene: POPDC2 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC2 were set to 41456958; 40409267
Phenotypes for gene: POPDC2 were set to Cardiac conduction disease with or without cardiomyopathy 2, MIM# 621367
Review for gene: POPDC2 was set to AMBER
Added comment: Multiple families reported with cardiac conduction and hypertrophic cardiomyopathy (rated GREEN).
AMBER rating given to this panel as there are only 2 reports of paediatric onset of HCM and cardiac conduction disorder (PMIDs: 41456958, 40409267).
Sources: Literature
Cardiomyopathy_Paediatric v1.0 IDS Gene migrated from ENSG00000010404 to ENSG00000010404 (gene set migration)
Cardiomyopathy_Paediatric v0.17 SHMT2 Zornitza Stark gene: SHMT2 was added
gene: SHMT2 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Cardiomyopathy_Paediatric v0.0 TAZ Zornitza Stark gene: TAZ was added
gene: TAZ was added to Cardiomyopathy_Paediatric. Sources: London South GLH,MetBioNet,Expert Review Green,NHS GMS,South West GLH
Mode of inheritance for gene: TAZ was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TAZ were set to 27604308
Phenotypes for gene: TAZ were set to Barth syndrome, 302060; Dilated Cardiomyopathy, X-Linked; Left Ventricular Noncompaction Cardiomyopathy; Neutropenia, muscle weakness, growth retardation; Non-compaction cardiomyopathy; HCM, mixed; Disorders of mitochondrial membrane lipids (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial lipid metabolism; Methylglutaconic aciduria type II, Barth syndrome (Organic acidurias); Barth syndrome
Cardiomyopathy_Paediatric v0.0 IDS Zornitza Stark gene: IDS was added
gene: IDS was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,MetBioNet,Expert Review Green
Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IDS were set to 27604308
Phenotypes for gene: IDS were set to MPS II, Hunter disease (Mucopolysaccharidoses); MUCOPOLYSACCHARIDOSIS TYPE 2; Mucopolysaccharidosis Type II; Mucopolysaccharidosis II, 309900