Application of next-generation sequencing of nuclear genes for mitochondrial disorders

Abstract

To date, more than 200 nuclear genes have been found to be linked to mitochondrial disorders [1, 2]. Initial application of next-generation sequencing (NGS) technology has been very successful for the identification of causative genes for mitochondrial disorders [3–7], similarly to other Mendelian diseases. Such advance is of outmost utility for a condition that is characterized by significant genetic and phenotypic heterogeneity with a very difficult diagnostic pathway. NGS for panels of targeted genes already known to cause mitochondrial disorders has recently become available for clinical testing. In addition, since many genes underpinning these conditions still need to be identified, some of the recent studies targeted the entire coding sequences of the genome (the whole exome), leading to the identification of mutations in novel nuclear genes, adding to the list of loci causing mitochondrial diseases. These studies have been successful even when only single affected families were available. As for many other genetic conditions, NGS is now serving the dual role of discovery and diagnostic tool [8] for mitochondrial disorders, exemplified by the studies described here. These roles, the opportunities, and challenges of NGS in the diagnosis of mitochondrial disorders are discussed in this chapter.