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Cardiomyopathy_Paediatric v1.253 MMUT Zornitza Stark Phenotypes for gene: MMUT were changed from 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. to methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, MONDO:0009612
Cardiomyopathy_Paediatric v1.229 DES Zornitza Stark Marked gene: DES as ready
Cardiomyopathy_Paediatric v1.229 DES Zornitza Stark Gene: des has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v1.229 DES Zornitza Stark Phenotypes for gene: DES were changed from Cardiomyopathy, dilated, 1I, to Cardiomyopathy, dilated, 1I, MIM# 604765
Cardiomyopathy_Paediatric v1.228 DES Zornitza Stark Publications for gene: DES were set to
Cardiomyopathy_Paediatric v1.227 DES Zornitza Stark Mode of inheritance for gene: DES was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cardiomyopathy_Paediatric v1.226 DES Zornitza Stark reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: None; Publications: 10430757, 20423733; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cardiomyopathy_Paediatric v1.200 PCCA Zornitza Stark Phenotypes for gene: PCCA were changed from 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 to propionic acidemia, MONDO:0011628
Cardiomyopathy_Paediatric v1.167 TMEM70 Richard Lin changed review comment from: Biallelic pathogenic variants in TMEM70 are associated with mitochondrial disease (ClinGen curation classified as definitive association). Paediatric onset cardiomyopathy, predominantly hypertrophic, and less commonly left ventricular noncompaction is well described.

PMID: 20335238 - Hypertrophic cardiomyopathy found in 76% (19/25 patients from 16 families) of neonatal onset TMEM70 associated ATP synthase deficiency. Twenty-four patients were homozygous for the c.317-2A>G mutation in the TMEM70 gene and one patient was compound heterozygote for c.[317-2A>G];[118_119insGT].
PMID: 26550569 - 4 affected sibs from one family with paediatric onset disease including noncompaction cardiomyopathy, 3 affected were homozygotes for TMEM70:c.317-2A>G, remaining affected child was not genotyped.
PMID: 27649480 - single case report of a male child who was homozygous for c.317-2A>G, diagnosed with neonatal onset hypertrophic cardiomyopathy.
PMID: 30899493 - infantile onset left ventricular noncompaction, compound heterozygous for a frameshift and a splice site variant c.[141delG];[316+1G>A]
PMID: 30950220 - 2 affected siblings who were homozygous for a frameshift variant c.105dupT (p.Val36Cysfs*52). Both were noted to have cardiac hypertrophy during antenatal fetal echocardiography.
PMID: 31729175 - 1 affected child who was homozygous for c.317-2A>G with dilated cardiomyopathy AND non compaction
PMID: 36751706 - 1 affected child with neonatal onset hyerptrophic cardiomyopathy and left ventricular non compaction, aortic dilatation. Homozygous for a missense VUS c.563T>C, p.(Leu188Pro), asserted by authors to be pathogenic based on a consistent metabolomic profile.; to: Biallelic pathogenic variants in TMEM70 are associated with mitochondrial disease (ClinGen curation classified as definitive association). Paediatric onset cardiomyopathy, predominantly hypertrophic, and less commonly left ventricular noncompaction is well described.

PMID: 20335238 - Hypertrophic cardiomyopathy found in 76% (19/25 patients from 16 families) of neonatal onset TMEM70 associated ATP synthase deficiency. All except one patient were homozygous for the c.317-2A>G mutation in the TMEM70 gene, with the remaining patient being compound heterozygote for c.[317-2A>G];[118_119insGT].
PMID: 26550569 - 4 affected sibs from one family with paediatric onset disease including noncompaction cardiomyopathy, 3 affected were homozygotes for TMEM70:c.317-2A>G, remaining affected child was not genotyped.
PMID: 27649480 - single case report of a male child who was homozygous for c.317-2A>G, diagnosed with neonatal onset hypertrophic cardiomyopathy.
PMID: 30899493 - infantile onset left ventricular noncompaction, compound heterozygous for a frameshift and a splice site variant c.[141delG];[316+1G>A]
PMID: 30950220 - 2 affected siblings who were homozygous for a frameshift variant c.105dupT (p.Val36Cysfs*52). Both were noted to have cardiac hypertrophy during antenatal fetal echocardiography.
PMID: 31729175 - 1 affected child who was homozygous for c.317-2A>G with dilated cardiomyopathy AND non compaction
PMID: 36751706 - 1 affected child with neonatal onset hyerptrophic cardiomyopathy and left ventricular non compaction, aortic dilatation. Homozygous for a missense VUS c.563T>C, p.(Leu188Pro), asserted by authors to be pathogenic based on a consistent metabolomic profile.
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 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 v1.147 PCCB Zornitza Stark Phenotypes for gene: PCCB were changed from 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 to propionic acidemia, MONDO:0011628
Cardiomyopathy_Paediatric v1.68 TREX1 Lucy Spencer gene: TREX1 was added
gene: TREX1 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: TREX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TREX1 were set to 25604658; 36581356
Phenotypes for gene: TREX1 were set to Aicardi-Goutieres syndrome 1, dominant and recessive MIM#225750
Review for gene: TREX1 was set to GREEN
Added comment: PMID: 25604658 infantile onset hypertrophic cardiomyopathy reported in 9/79 individuals with TREX1 related Aicardi-Goutieres syndrome. This paper includes both recessive and dominant TREX1 patients, it is unclear which have HCM.

PMID 36581356 reports one proband with Aicardi-Goutieres syndrome diagnosed with cardiomyopathy in utero. The proband was homozygous for a TREX1 frameshift variant.
Sources: Literature
Cardiomyopathy_Paediatric v1.64 NAA10 Rylee Peters gene: NAA10 was added
gene: NAA10 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: NAA10 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: NAA10 were set to 40304357; 40234403; 38335407; 37441566; 37130971; 33335012; 32864149
Phenotypes for gene: NAA10 were set to NAA10-related syndrome, MONDO:0100124
Review for gene: NAA10 was set to GREEN
Added comment: NAA10-related neurodevelopmental syndrome phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities. Multiple families also reported with early‑onset cardiomyopathy, predominantly hypertrophic cardiopmyopathy phenotype.
Sources: Literature
Cardiomyopathy_Paediatric v1.58 BOLA3 Rylee Peters gene: BOLA3 was added
gene: BOLA3 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: BOLA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BOLA3 were set to 40273865
Phenotypes for gene: BOLA3 were set to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, MIM#614299
Review for gene: BOLA3 was set to GREEN
Added comment: PMID: 40273865 describes several unrelated families with biallelic BOLA3 variants causing early‑infantile multiple mitochondrial dysfunction syndrome 2 (MMDS2) that frequently includes hypertrophic cardiomyopathy.
Sources: Literature
Cardiomyopathy_Paediatric v1.54 TRIM37 Sarah Milton gene: TRIM37 was added
gene: TRIM37 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: TRIM37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM37 were set to 41702694; 38116000; 36742244
Phenotypes for gene: TRIM37 were set to mulibrey nanism, MONDO:0009664
Review for gene: TRIM37 was set to GREEN
Added comment: Mulibrey nanism (MUL) is a rare autosomal recessive growth disorder with prenatal onset and characteristic facial features, along with occasional restrictive cardiomyopathy/restrictive pericarditis, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor. Numerous case reports with biallelic variants in the TRIM37 gene, which encodes a peroxisomal protein.
Sources: Literature
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
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
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
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
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
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
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
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
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
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
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
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 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
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
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.
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,