Increasingly, whole exome sequencing has been critical in resolving molecular causes of unknown metabolic or mitochondrial disorders. Diodato et al (Hum Mutat. 2014 Aug;35(8):983-9) used WES to identify homozygous mutations in VARS2 (Valyl tRNA synthetase) in one patient seizures and deficiency mitochondrial respiratory chain complex I, and compound heterozygous mutations in TARS2 (threonyl-tRNA synthetase) in siblings with hypotonia, severe psychomotor delay and multiple respiratory chain defects.
The mitochondtial tRNA synthetases are an increasingly being implicated in a wide range of mitochondrial disorders and encephalopathies. However, the genes for these tRNAs are not included on most mitochondrial disease gene testing panels. Thus, whole exome sequencing is currently the most efficient way to diagnose them.
Hilary Vernon, MD PhD