Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

•Able to diagnose four patients with mitochondrial disorders through exome sequencing•Concomitantly sequenced the nuclear exome and mitochondrial genome•Accurately detected homoplasmic and heteroplasmic variants from the mtDNA•Exome sequencing produced a molecular dx when conventional molecular testing failed.

Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.