Key result
Combined nuclear and mitochondrial sequencing reveals synergistic variants disrupting myocardial bioenergetics in pediatric cardiomyopathy.
Why the study?
Many cases of pediatric cardiomyopathy have no known etiology, prompting investigation into whether mitochondrial genome defects contribute to disease pathogenesis.
Does whole mitochondrial DNA sequencing combined with nuclear gene sequencing identify additional pathogenic variants in pediatric patients with primary non-syndromic cardiomyopathy?
Observational (n=58)
No
Does whole mitochondrial DNA sequencing combined with nuclear gene sequencing identify additional pathogenic variants in pediatric patients with primary non-syndromic cardiomyopathy?
Integrating whole mitochondrial DNA sequencing with nuclear gene panels reveals that mitochondrial variants may act synergistically with nuclear defects to drive pediatric cardiomyopathies.
Answers are grounded in this paper and cite their sources.
mtDNA sequencing may detect missed variants in unexplained pediatric cardiomyopathy; leaves open its diagnostic role pending validation.
Mitochondrial defects can lead to cardiomyopathies, which can be particularly severe in children. However, many cases of pediatric cardiomyopathy have no known etiology. To address this, we sought to explore if mitochondrial genome defects might be a contributor, as this could offer insights into disease mechanisms and guide targeted interventions. We first sequenced cardiomyopathy-related genes in twenty-seven pediatric patients diagnosed with primary non-syndromic cardiomyopathy and performed whole mtDNA sequencing in both patients and thirty-one healthy controls. The initial sequencing identified pathogenic variants in seven patients but subsequent mtDNA sequencing revealed additional insights. Specifically, a variant in FOXRED1, encoding FAD-dependent oxidoreductase domain-containing protein-1 which functions in mitochondrial complex I stability, and another variant in cytochrome c oxidase-I, MT-CO1, crucial for aerobic metabolism, were identified in two siblings with hypertrophic cardiomyopathy. In another case with hypertrophic cardiomyopathy, a variant in cytochrome b, MT-CYB, is likely a key factor in the abnormal contraction of cardiac muscle contraction. Furthermore, a novel 12 S rRNA variant was found in a patient with left ventricular non-compaction, and this offers a promising explanation for the pathogenesis, given the gene's high expression in the left ventricle. Taken together, mtDNA variants act synergistically with others, potentially disrupting myocardial bioenergetics.
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Temena et al. (2025) conducted an observational in Pediatric cardiomyopathies (n=58). Mitochondrial and nuclear genome variants vs. Healthy controls was evaluated on Identification of pathogenic nuclear and mitochondrial DNA variants. Combined nuclear and mitochondrial DNA sequencing in 27 pediatric cardiomyopathy patients identified pathogenic nuclear variants in 7 patients and revealed additional mitochondrial variants that may synergistically disrupt myocardial bioenergetics.
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