Rare missense substitutions in the mitochondrial DNA genes in patients with ventricular tachycardia

   Human mitochondrial DNA (mtDNA) exhibits high population-level polymorphism. While certain pathogenic mtDNA variants are known to cause hereditary mitochondrial syndromes, often presenting with cardiac arrhythmias, life-threatening ventricular tachycardia (VT) itself is a major risk factor for sudden death in cardiovascular diseases.

   The aim of the work was to study rare (“private”) missense substitutions in the mtDNA of patients with documented episodes of ventricular tachycardia in comparison with patients with ischemic heart disease without life-threatening heart arrhythmias and individuals without clinical manifestations of cardiovascular diseases.

   The sequencing of mtDNA was performed using high-throughput sequencing methods. Specialized algorithms predicting the effect of gene variants were used to assess the effect of missense substitutions. Comparative analysis of the spectrum of the identified amino acid substitutions in the studied groups showed that about 40 % of the individuals in all three groups were carriers of “private” missense variants in mtDNA. However, among such substitutions, the variants classified by the APOGEE2 predictor as “variants of uncertain significance” (VUS) were more common in the group of patients with heart arrhythmias than in the control group, where “private” missense substitutions of the VUS category were not detected (p = 0.0063 for Fisher’s exact test). In addition, the groups differed in their phred-ranked Combined Annotation Dependent Depletion (CADD) scores, which were lower for individuals in the control group. The results indicate that rare mtDNA variants may contribute to predisposition to cardiovascular disease – in particular, to the risk of developing ventricular tachycardia by some patients.

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