Discovering rare diseases: mutation in the Nuclear Encoded Mitochondrial Isoleucyl tRNA-Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness and Peripheral Neuropathy or with Leigh Syndrome.

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here we report a novel disorder in three adult patients with a phenotype including cataracts, short stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy and skeletal dysplasia. Using SNP genotyping and whole exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh Syndrome. This is the first report of clinical findings associated with IARS2 mutations. This article is protected by copyright. All rights reserved.

Hum Mutat. 2014 Aug