IMPORTANCE: Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Patients with multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis, with many not yet linked to human disease. OBJECTIVE: To determine the molecular basis of multiple respiratory chain complex deficiencies. DESIGN: We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005-2012. All had biochemical evidence of multiple respiratory chain complex defects, and no primary pathogenic mitochondrial DNA mutation. Whole exome sequencing was performed using 62Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. PARTICIPANTS: 53 patients with biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. RESULTS: Presumptive causal variants were identified in 28 patients (53%, 95% CI=39-67), and possible causal variants were identified in 4 (8%, 95% CI=2-18). Together these account for 32 patients (60%, 95% CI=46-74), and involved 18 different genes. These included recurrent mutations in RMND1, AARS2 and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1 and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1, and cardiomyopathy with AARS2, and MTO1. However, “classical” features were absent in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations, and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%, 95% CI=26-54). CONCLUSIONS AND RELEVANCE: Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically-defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study will be required in independent patient populations to determine the utility of this approach in comparison to traditional diagnostic methods.
