Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

ABSTRACT Myocardial defects, originating from disruptions in genes affecting mitochondrial proteins interacting with others, have received limited research attention. In our study involving 27 pediatric cardiomyopathy patients, we explored mitochondrial and nuclear genes for four main cardiomyopathy subtypes. Sequencing cardiomyopathy-associated genes in patients was followed by whole mtDNA sequencing in these individuals, with 31 healthy pediatric controls for the latter part. Our findings uncovered significant pathogenic variants: MYH7 variants in three hypertrophic cardiomyopathy cases, a notable TNNC1 variant inherited interestingly in an autosomal recessive manner in two related restrictive cardiomyopathy patients, and a pathogenic TRDN variant in a left-ventricular non-compaction patient. Both a variant in FOXRED1, functioning in mitochondrial complex I stability, and a MT-CO1 variant were detected in two siblings, influencing early onset together. Additionally, a novel MT-RNR1 variant (m.684T>C) in one case might explain the phenotype. Our study highlights how both mtDNA and nDNA variants could have interconnected roles in understanding cardiomyopathy genetics. This study emphasizes that the functional studies are needed to recognize this dual relationship within bioenergetic pathways in cardiac muscle.