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| Cardiomyopathy_Paediatric v1.47 | LETM1 |
Sarah Milton changed review comment from: PMID 36055214 reports 18 individuals from 11 families (collapsed to 9 independent families) with biallelic LETM1 loss-of-function or missense variants presenting with childhood-onset mitochondrial disease that occasionally includes hypertrophic cardiomyopathy (36% of cases). Sources: Literature; to: PMID 36055214 reports 18 individuals from 11 families (collapsed to 9 independent families) with biallelic LETM1 loss-of-function or missense variants presenting with childhood-onset mitochondrial disease that occasionally includes paediatric onset hypertrophic cardiomyopathy (36% of cases). Sources: Literature |
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| Cardiomyopathy_Paediatric v1.46 | LETM1 |
Sarah Milton gene: LETM1 was added gene: LETM1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LETM1 were set to 36055214 Phenotypes for gene: LETM1 were set to neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, MONDO:0859304 Review for gene: LETM1 was set to GREEN Added comment: PMID 36055214 reports 18 individuals from 11 families (collapsed to 9 independent families) with biallelic LETM1 loss-of-function or missense variants presenting with childhood-onset mitochondrial disease that occasionally includes hypertrophic cardiomyopathy (36% of cases). Sources: Literature |
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| Cardiomyopathy_Paediatric v1.37 | SLC6A8 |
Lucy Spencer gene: SLC6A8 was added gene: SLC6A8 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: SLC6A8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SLC6A8 were set to 34050321 Phenotypes for gene: SLC6A8 were set to Cerebral creatine deficiency syndrome 1 MIM#300352 Review for gene: SLC6A8 was set to AMBER Added comment: PMID 34050321 describe 2 individuals with creatine transporter deficiency and mild cardiomyopathy and state that a few more patients in their cohort have signed of 'developing cardiomyopathy' on ECG/echo. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.31 | MTO1 |
Lucy Spencer gene: MTO1 was added gene: MTO1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: MTO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTO1 were set to 29331171 Phenotypes for gene: MTO1 were set to Combined oxidative phosphorylation deficiency 10 MIM#614702 Review for gene: MTO1 was set to GREEN Added comment: PMID 29331171 describe HCM as the most common clinical feature at initial presentation in their cohort of 34 individuals with MTO1 deficiency. 15 patients had HCM at initial presentation, and over time it developed into a total of 27/34 patients with HCM. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.22 | VARS2 |
Zornitza Stark gene: VARS2 was added gene: VARS2 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VARS2 were set to 40563223; 33937156; 31623496; 30458719; 29314548; 27502409 Phenotypes for gene: VARS2 were set to combined oxidative phosphorylation defect type 20, MONDO:0014397 Review for gene: VARS2 was set to GREEN Added comment: PMID 29314548 reports 13 patients from nine unrelated families with biallelic VARS2 loss‑of‑function variants presenting with early‑onset mitochondrial encephalomyopathy and hypertrophic cardiomyopathy. PMID 40563223 adds four patients from three unrelated families with similar phenotype and demonstrates rescue of a Xenopus VARS2 knockout. Single families with the same phenotype are further described in PMID 27502409, PMID 31623496, PMID 30458719 and PMID 33937156, all harbouring biallelic VARS2 variants and severe paediatric cardiomyopathy. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.13 | RBM10 |
Zornitza Stark gene: RBM10 was added gene: RBM10 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: RBM10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: RBM10 were set to 30450804 Phenotypes for gene: RBM10 were set to TARP syndrome, MONDO:0010711 Review for gene: RBM10 was set to GREEN Added comment: PMID 30450804 reports one individual with X-linked loss-of-function RBM10 variant presenting with hypertrophic obstructive cardiomyopathy as part of TARP syndrome. The syndrome includes talipes, atrial septal defect, Robin sequence and additional anomalies. Paper reviews literature and identifies two previous reports. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.4 | DPM3 |
Zornitza Stark gene: DPM3 was added gene: DPM3 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: DPM3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPM3 were set to 35932216 Phenotypes for gene: DPM3 were set to DPM3-congenital disorder of glycosylation, MONDO:0013049 Review for gene: DPM3 was set to AMBER Added comment: PMID 35932216 reports 5 individuals from 4 families with biallelic homozygous missense DPM3 c.221A>G (p.Tyr74Cys) variants presenting with muscle weakness, developmental delay/intellectual disability, seizures, white‑matter abnormalities and childhood‑onset cardiomyopathy. Note that most individuals reported with DPM3 variants have had a predominantly skeletal muscle phenotype. AMBER rating as only a single variant has been associated with this much more extensive multi-system phenotype that includes paediatric cardiomyopathy. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.0 | DES | Gene migrated from ENSG00000175084 to ENSG00000175084 (gene set migration) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiomyopathy_Paediatric v0.204 | MRPS36 |
Krithika Murali gene: MRPS36 was added gene: MRPS36 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS36 were set to PMID: 41018056; 38685873 Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related Review for gene: MRPS36 was set to AMBER Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported. Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.102 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Cardiomyopathy_Paediatric. Sources: Literature founder tags were added to gene: RNF220. Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.65 | ELAC2 |
John Christodoulou gene: ELAC2 was added gene: ELAC2 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: ELAC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ELAC2 were set to PMID: 23849775: PMID: 28441660 Phenotypes for gene: ELAC2 were set to cardiomyopathy; hypotonia; growth failure; dev delay; microcephaly; sensorineural deafness; brain MRI abnormalities Penetrance for gene: ELAC2 were set to Complete Review for gene: ELAC2 was set to GREEN Added comment: 5 cases from 3 unrelated families described in the first paper cited above see OMIM 615440 Sources: Literature |
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| Cardiomyopathy_Paediatric v0.65 | PMM2 |
John Christodoulou gene: PMM2 was added gene: PMM2 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMM2 were set to PMID: 28954837: PMID: 33388235 Phenotypes for gene: PMM2 were set to hypotonia; intellectual disability; cerebellar signs; pericarditis; cardiomyopathy; cardiac malformation; chronic diarrhoea; protein-losing enteropathy; ascites; cover failure; nephrotic syndrome; hydros Penetrance for gene: PMM2 were set to Complete Review for gene: PMM2 was set to RED Added comment: OMIM 212065 The two papers cited above are both review papers - the first describes a cohort of 96 patients - 9 had cardiomyopathy Sources: Literature |
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| 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 |
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| Cardiomyopathy_Paediatric v0.0 | PCCB |
Zornitza Stark gene: PCCB was added gene: PCCB was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,South West GLH,MetBioNet,Expert Review Green Mode of inheritance for gene: PCCB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCCB were set to 27604308 Phenotypes for gene: PCCB were set to as PCCA (metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections); Propionic acidemia; Propionicacidemia 606054; Propionic aciduria; Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; DCM; Propionic aciduria (Organic acidurias); Hypertrophic-hypocontractile cardiomyopathy; Propionicacidemia |
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| Cardiomyopathy_Paediatric v0.0 | PCCA |
Zornitza Stark gene: PCCA was added gene: PCCA was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,South West GLH,MetBioNet,Expert Review Green Mode of inheritance for gene: PCCA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCCA were set to 27604308 Phenotypes for gene: PCCA were set to metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections; Propionic acidemia; Propionicacidemia 606054; Propionic aciduria; Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; DCM; Propionic aciduria (Organic acidurias); Hypertrophic-hypocontractile cardiomyopathy; Propionicacidemia |
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| Cardiomyopathy_Paediatric v0.0 | MUT |
Zornitza Stark gene: MUT was added gene: MUT was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,South West GLH,MetBioNet,Expert Review Green Mode of inheritance for gene: MUT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MUT were set to 27604308 Phenotypes for gene: MUT were set to Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; Methylmalonic aciduria; Methylmalonic aciduria, mut(0) type 251000; DCM; Methylmalonyl-CoA mutase deficiency (Organic acidurias); Hypertrophic-hypocontractile cardiomyopathy; metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections. |
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| Cardiomyopathy_Paediatric v0.0 | DES |
Zornitza Stark gene: DES was added gene: DES was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,South West GLH,Expert Review Green Mode of inheritance for gene: DES was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: DES were set to Cardiomyopathy, dilated, 1I, |
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