A novel homozygous mutation in SUCLA2 gene identified by exome sequencing.

Mitochondrial disorders with multiple mitochondrial respiratory chain (MRC) enzyme deficiency and depletion of mitochondrial DNA (mtDNA) are autosomal recessive conditions due to mutations in several nuclear genes necessary for proper mtDNA maintenance. In this report, we describe two Italian siblings presenting with encephalomyopathy and mtDNA depletion in muscle. By whole exome-sequencing and prioritization of candidate genes, we identified a novel homozygous missense mutation in the SUCLA2 gene in a highly conserved aminoacid residue. Although a recurrent mutation in the SUCLA2 gene is relatively frequent in the Faroe Islands, mutations in other populations are extremely rare. In contrast with what has been reported in other patients, methyl-malonic aciduria, a biomarker for this genetic defect, was absent in our proband and very mildly elevated in her affected sister. This report demonstrates that next-generation technologies, particularly exome-sequencing, are user friendly, powerful means for the identification of disease genes in genetically and clinically heterogeneous inherited conditions, such as mitochondrial disorders.