Pathogenic mitochondrial genome variation, heteroplasmy thresholding and mitochondrial constraint measures in a healthy older cohort

Mitochondrial diseases (MDs) are clinically heterogeneous rendering ascertainment challenging. Estimates of pathogenic mitochondrial DNA (mtDNA) variants in the population range from 1 in 200 to 1 in 4,000 individuals. Inclusion of mtDNA sequencing in genomic databases facilitates comprehensive estimation of mtDNA variation. However, interpretation of low heteroplasmy variation is complex, due in part to misalignment of nuclear mitochondrial DNA transcripts (NUMTs), whilst conservative heteroplasmy thresholds likely omit relevant variation. Cumulative burden of mtDNA variation contributes to aging and neurodegeneration, and recent characterisation of mitochondrial genome constraint allows qu