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| Cardiomyopathy_Paediatric v1.50 | QRSL1 |
Sarah Milton gene: QRSL1 was added gene: QRSL1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: QRSL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: QRSL1 were set to 35894854; 30283131; 29440775 Phenotypes for gene: QRSL1 were set to Combined oxidative phosphorylation deficiency 40, MIM#618835 Review for gene: QRSL1 was set to GREEN Added comment: PMID 29440775, PMID 30283131 and PMID 35894854 report a number of individuals with biallelic loss-of-function QRSL1 variants resulting in combined oxidative phosphorylation deficiency 40, characterised by a multisystem mitochondrial disease featuring early‑onset (prenatal/neonatal) hypertrophic cardiomyopathy. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.48 | NDUFA5 |
Sarah Milton gene: NDUFA5 was added gene: NDUFA5 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: NDUFA5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFA5 were set to 41916321 Phenotypes for gene: NDUFA5 were set to Mitochondrial disease, MONDO:0044970 Review for gene: NDUFA5 was set to AMBER Added comment: PMID 41916321 reports 4 individuals from 3 unrelated families with biallelic loss-of-function NDUFA5 variants presenting with early onset multisystem mitochondrial disorder with complex I deficiency. One individual had hypertrophic cardiomyopathy and one had slight biventricular hypertrophy. Paediatric onset HCM is likely to be a feature of this disorder given it is seen in other complex I deficiencies however few patients have been reported thus far. Sources: Literature |
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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 v1.44 | FBXL4 |
Sarah Milton gene: FBXL4 was added gene: FBXL4 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXL4 were set to 28940506 Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), MIM#615471 Review for gene: FBXL4 was set to GREEN Added comment: PMID 28940506 reports 87 individuals from 72 unrelated families with biallelic loss‑of‑function FBXL4 variants causing mitochondrial DNA depletion syndrome 13. An early onset multisystem disease characterised by lactic acidosis, developmental delay, hypotonia and hypertrophic cardiomyopathy in ~20 % of cases. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.42 | COQ2 |
Sarah Milton gene: COQ2 was added gene: COQ2 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: COQ2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COQ2 were set to 40929079; 33677064 Phenotypes for gene: COQ2 were set to Coenzyme Q10 deficiency, primary, 1, MIM#607426 Review for gene: COQ2 was set to GREEN Added comment: Biallelic loss of function in COQ2 results in a wide spectrum of disease with the most severe being multisystem neonatal onset form with severity of presentation correlating to level of residual enzyme activity. Hypertrophic cardiomyopathy has been reported in a small number of individuals with the severe neonatal form. Note the small number of papers asserting a degree of treatment response to COQ10/4-hydroxybenzoic acid Sources: Literature |
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| Cardiomyopathy_Paediatric v1.41 | CHKB |
Sarah Milton gene: CHKB was added gene: CHKB was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: CHKB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKB were set to 39465137; 34962344; 33623274; 27123443; 26067811; 25740612 Phenotypes for gene: CHKB were set to Muscular dystrophy, congenital, megaconial type, MIM# 602541 Review for gene: CHKB was set to GREEN Added comment: PMID 26067811, PMID 34962344, PMID 25740612, PMID 27123443, PMID 39465137 and PMID 33623274 collectively report a number of individuals with biallelic loss‑of‑function CHKB variants causing megaconial congenital muscular dystrophy, frequently presenting with early‑onset dilated cardiomyopathy together with muscle weakness, developmental delay and ichthyosis. 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 v1.35 | PIGA |
Lucy Spencer gene: PIGA was added gene: PIGA was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: PIGA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: PIGA were set to 32452540; 37489290 Phenotypes for gene: PIGA were set to Multiple congenital anomalies-hypotonia-seizures syndrome 2 MIM#300868 Review for gene: PIGA was set to AMBER Added comment: PMID 32452540 lists cardiomyopathy as a feature in 3 of their 76 patients with multiple congenital anomalies-hypotonia-seizures syndrome. PMID 37489290 reports 4 unrelated patients with PIGA encephalopathy and DCM (1 overlaps with PMID 32452540). Also report a further 2 individuals with PIGA-related encephalopathy and left/right ventricular hypertrophy. 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 v1.29 | MED12 |
Lucy Spencer gene: MED12 was added gene: MED12 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: MED12 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: MED12 were set to 39045790 Phenotypes for gene: MED12 were set to Hardikar syndrome MIM#301068 Review for gene: MED12 was set to GREEN Added comment: PMID 39045790 in a cohort of 10 individuals with Hardikar syndrome, 6 had cardiomyopathy all under 15 years old. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.20 | TRMT5 |
Zornitza Stark gene: TRMT5 was added gene: TRMT5 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: TRMT5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRMT5 were set to 26189817 Phenotypes for gene: TRMT5 were set to combined oxidative phosphorylation defect type 26, MONDO:0014684 Review for gene: TRMT5 was set to AMBER Added comment: PMID 26189817 reports 2 individuals from 2 families with biallelic TRMT5 variants presenting with childhood‑onset hypertrophic cardiomyopathy and multisystemic mitochondrial disease. Sources: Literature |
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| Cardiomyopathy_Paediatric v1.18 | SUCLG1 |
Zornitza Stark gene: SUCLG1 was added gene: SUCLG1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: SUCLG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUCLG1 were set to 26475597 Phenotypes for gene: SUCLG1 were set to mitochondrial DNA depletion syndrome 9, MONDO:0009504 Review for gene: SUCLG1 was set to GREEN Added comment: PMID 26475597 reports 21 individuals from 5 families with biallelic SUCLG1 variants presenting with mitochondrial DNA depletion syndrome 9, characterised by infantile encephalomyopathy, lactic acidosis, hypotonia and hypertrophic cardiomyopathy. Cardiomyopathy was present in around 15%. 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 v1.2 | ATP5PO |
Zornitza Stark gene: ATP5PO was added gene: ATP5PO was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: ATP5PO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP5PO were set to 40913360; 35621276 Phenotypes for gene: ATP5PO were set to mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MONDO:0957255 Review for gene: ATP5PO was set to AMBER Added comment: PMID 40913360 and PMID 35621276 report 4 individuals from 3 families with homozygous splice variant c.87+3A>G in ATP5PO causing early‑onset hypertrophic cardiomyopathy, encephalopathy and hypotonia. The phenotype aligns with mitochondrial complex V (ATP synthase) deficiency, nuclear type 7. AMBER rating as manifestation only linked to this one specific variant; founder effect? Sources: Literature |
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| Cardiomyopathy_Paediatric v1.0 | IDUA | Gene migrated from ENSG00000127415 to ENSG00000127415 (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 v0.200 | MYO19 |
Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather. MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated. All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent. It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy. Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather. MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated. All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent. It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.200 | MYO19 |
Lucy Spencer gene: MYO19 was added gene: MYO19 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYO19 were set to 40634996 Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related Review for gene: MYO19 was set to RED Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather. MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated. All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent. It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.191 | GTPBP3 |
Zornitza Stark gene: GTPBP3 was added gene: GTPBP3 was added to Cardiomyopathy_Paediatric. Sources: Expert Review Mode of inheritance for gene: GTPBP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP3 were set to 34276756; 25434004 Phenotypes for gene: GTPBP3 were set to Combined oxidative phosphorylation deficiency 23 MIM#616198 Review for gene: GTPBP3 was set to GREEN Added comment: Clinical presentation: early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. At least 12 unrelated individuals reported. Sources: Expert Review |
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| Cardiomyopathy_Paediatric v0.148 | TOR1AIP1 |
Zornitza Stark gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 24856141; 27342937; 32055997; 25425325 Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900 Review for gene: TOR1AIP1 was set to GREEN Added comment: At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here. Muscular dystrophy is the prominent feature of the disease presentation observed in at least one case individual each family, but specifically proximal limb-girdle dystrophy was recorded in 4 unrelated kindreds. Additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam). Age of onset for cardiomyopathy was variable ranging from childhood to adulthood. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.146 | SPRED2 |
Zornitza Stark gene: SPRED2 was added gene: SPRED2 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPRED2 were set to 34626534 Phenotypes for gene: SPRED2 were set to Noonan syndrome 14, MIM# 619745 Review for gene: SPRED2 was set to AMBER Added comment: Four individuals from three families reported with bi-allelic variants and a Noonan-like phenotype. One individual has HCM, and another asymmetrical interventricular septal hypertrophy. Sources: Literature |
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| Cardiomyopathy_Paediatric v0.123 | CRLS1 |
Michelle Torres gene: CRLS1 was added gene: CRLS1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: CRLS1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CRLS1 were set to 35147173 Review for gene: CRLS1 was set to AMBER Added comment: - Three families (4 individuals) with cardiolipin deficiency. - Two families (one consanguineous with 2 affected siblings) with homozygous the p.(Ile109Asn) had infantile progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. - The fourth individual cHet p.(Ala172Asp) and p.(Leu217Phe) presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. - Functional studies on patient cells showed increased levels of the substrate of CRLS1 and impaired mitochondrial morphology and biogenesis *Two individuals presented cardiac defects: one with LVNC, biventricular systolic dysfunction and evolved to HCM; the other one had biventricular dysfunction Sources: Literature |
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| Cardiomyopathy_Paediatric v0.111 | COQ4 |
Zornitza Stark gene: COQ4 was added gene: COQ4 was added to Cardiomyopathy_Paediatric. Sources: Expert Review Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COQ4 were set to 25658047; 26185144; 33704555 Phenotypes for gene: COQ4 were set to Coenzyme Q10 deficiency, primary, 7, MIM# 616276 Review for gene: COQ4 was set to GREEN Added comment: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. HCM reported in multiple individuals. At least 9 unrelated families reported. Sources: Expert Review |
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| Cardiomyopathy_Paediatric v0.103 | JPH2 |
Zornitza Stark changed review comment from: MODERATE evidence by ClinGen working group. Via ClinGen: Associated with hypertrophic cardiomyopathy in 16 probands in 5 publications with some functional evidence in support (expression studies, in vitro assays, animal models). Conflicting evidence for missense variants in particular: one of the variants p.Gly505Ser is present in >500 individuals in gnomad, including 7 homozygotes, and another novel missense variant was observed in an 86-year-old man, diagnosed with hypertrophic cardiomyopathy, in whom echocardiography and cardiac magnetic resonance imaging strongly suggested amyloidosis to be the underlying cause.; to: Association with HCM: MODERATE evidence by ClinGen working group. Via ClinGen: Associated with hypertrophic cardiomyopathy in 16 probands in 5 publications with some functional evidence in support (expression studies, in vitro assays, animal models). Conflicting evidence for missense variants in particular: one of the variants p.Gly505Ser is present in >500 individuals in gnomad, including 7 homozygotes, and another novel missense variant was observed in an 86-year-old man, diagnosed with hypertrophic cardiomyopathy, in whom echocardiography and cardiac magnetic resonance imaging strongly suggested amyloidosis to be the underlying cause. |
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| Cardiomyopathy_Paediatric v0.90 | RPL3L |
Zornitza Stark gene: RPL3L was added gene: RPL3L was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPL3L were set to 32514796; 32870709 Phenotypes for gene: RPL3L were set to Cardiomyopathy, dilated, 2D, MIM# 619371; Neonatal dilated cardiomyopathy Review for gene: RPL3L was set to GREEN Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype. PMID: 32870709 - 1 hom patient w/ neonatal DCM Sources: Literature |
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| Cardiomyopathy_Paediatric v0.49 | PLD1 |
Zornitza Stark gene: PLD1 was added gene: PLD1 was added to Cardiomyopathy_Paediatric. Sources: Literature Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLD1 were set to 27799408; 33645542 Phenotypes for gene: PLD1 were set to Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy Review for gene: PLD1 was set to GREEN Added comment: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%). 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 v0.2 | MRAS |
Zornitza Stark gene: MRAS was added gene: MRAS was added to Cardiomyopathy_Paediatric. Sources: Expert list Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MRAS were set to 28289718; 31173466; 31108500; 31173466 Phenotypes for gene: MRAS were set to Noonan syndrome, MIM#618499 Review for gene: MRAS was set to GREEN Added comment: At least 6 unrelated individuals reported with NS, cardiomyopathy specifically reported Sources: Expert list |
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| Cardiomyopathy_Paediatric v0.0 | IDUA |
Zornitza Stark gene: IDUA was added gene: IDUA was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,MetBioNet,Expert Review Green Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IDUA were set to 27604308 Phenotypes for gene: IDUA were set to Scheie syndrome; Hurler-Scheie syndrome; Mucopolysaccharidosis type 1H; Mucopolysaccharidosis Ih/s, 607015; Mucopolysaccharidosis Ih, 607014; Mucopolysaccharidosis type 1S; Hurler syndrome; MPS I, Hurler, Scheie disease (Mucopolysaccharidoses); Mucopolysaccharidosis, Type I; Mucopolysaccharidosis type 1H/S; Mucopolysaccharidosis Is, 607016 |
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