Whole exome sequencing-based discovery of causative genes

Abstract

Leigh syndrome (LS) is one of the most common mitochondrial disorders, which is characterized by various neurodegenerative features and bilateral symmetric central nervous system lesions. About 30% of LS have mitochondrial DNA mutations, while the remainder is thought to have nuclear DNA mutations. To date, mutations in more than 75 genes have been identified in both mitochondrial and nuclear genome. The aim of this study was to discover the causative nuclear genes in LS by using whole exome sequencing. We included 35 patients (34 families) who were diagnosed with LS at the Seoul National University Childrens Hospital from 2001 to 2015. Diagnosis was based on characteristic clinical presentation and neuroradiological findings, which was supported by biochemical features suggestive of mitochondrial dysfunction. They had no mitochondrial DNA mutations identified. Pathogenic variants in genes previously shown to cause LS were identified in 14 patients (14/34=41.2%). The results showed the genetic complexity: NDUFS1 (1), NDUFV1 (1), NDUFAF6 (2), SURF1 (2), SLC19A3 (2), ECHS1 (2), PNPT1 (1), IARS2 (2), and NARS2 (1). All the pathogenic variants identified in this study, except three, have never been reported. Of note, mutations in genes associated with mitochondrial translation were frequently observed (4/14=28.6%). Additionally there were two novel genes identified in 3 patients (3/34=8.8%), of which the functions have not been discovered in human: APOA1BP (1) and VPS13D (2). There was poor genotype-phenotype correlation in view of clinical, neuroradiological, and biochemical features, even after reviewing the reported cases with the same causative genes. Our findings suggest that LS has a genetic heterogeneity, showing mutations in mitochondrial translation and valine metabolism as well as oxidative phosphorylation system subunits or assembly factors. Whole exome sequencing broadened the genetic spectrum of LS, showing the clinical utility to identify the causative genes in patients with LS. Discovery of molecular defects in Korean LS might prompt us to develop the gene panel for Korean LS.