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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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