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| Paediatric or syndromic cardiomyopathy v8.14 | DNM1L |
Agnese Zarina gene: DNM1L was added gene: DNM1L was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: DNM1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DNM1L were set to PMID: 31587467, 39063023, 39859560, 35914810, 20585624. Phenotypes for gene: DNM1L were set to DNM1L-related mitochondrial fission disorder with cardiomyopathy; hypertrophic cardiomyopathy; encephalocardiomyopathy. Penetrance for gene: DNM1L were set to Complete Mode of pathogenicity for gene: DNM1L was set to Other Review for gene: DNM1L was set to GREEN Added comment: I recommend the inclusion of DNM1L in the Cardiomyopathy Panel with a Green rating, particularly for childhood-onset and syndromic cardiomyopathies. DNM1L encodes dynamin-related protein 1 (DRP1), a key regulator of mitochondrial and peroxisomal fission. Pathogenic DNM1L variants are associated with mitochondrial fission disorders, predominantly characterised by neurological manifestations. However, accumulating clinical and functional evidence demonstrates that cardiomyopathy is an important, potentially life-threatening manifestation of DNM1L-related disease. Cardiomyopathy has been reported in multiple unrelated patients carrying different de novo heterozygous pathogenic DNM1L variants, including p.(Glu410Lys), p.(Ser39Asn), and p.(Gly401Ser). Reported cardiac manifestations include hypertrophic cardiomyopathy, severe mitochondrial cardiomyopathy, progressive heart failure, cardiogenic shock, and fatal outcomes. Importantly, the association is supported by functional studies demonstrating impaired mitochondrial dynamics, altered DRP1 function, and dominant-negative effects. Experimental animal models have also demonstrated that DNM1L dysfunction can directly cause cardiomyopathy. These findings provide clinical, molecular, and functional evidence supporting DNM1L as a cardiomyopathy-associated gene. The available evidence is particularly relevant to early-onset cardiomyopathy associated with neurological or other mitochondrial manifestations. Based on reports from at least three unrelated patients with cardiomyopathy, together with functional and experimental evidence, I recommend a Green (diagnostic-grade) rating for DNM1L in the Cardiomyopathy Panel, consistent with the Genomics England PanelApp criteria. Mode of inheritance: MONOALLELIC, autosomal dominant (primarily de novo), for the reported cardiomyopathy-associated phenotype. Biallelic is not proven for cardiomyopathies. Sources: Literature |
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