Identification by whole-exome sequencing of two novel LARS2 mutations in an Italian family with Perrault syndrome

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and premature ovarian failure (POF) in females, and by progressive hearing loss in both genders. Recently, mutations in four genes (i.e. HSD17B4, HARS2, CLPP, and LARS2) were found to be responsible for PRLTS, although they do not account for all cases of this genetically heterogeneous condition. In this study, we used whole-exome sequencing (WES) to identify the pathogenic variants responsible for PRLTS in an Italian pedigree with two affected siblings (one female and one male). All five family members were subjected to WES using the SeqCapEZ Exome v2 kit (Roche) and the HiSeq2000 platform (Illumina). Data analysis highlighted compound heterozygosity, in both patients, for two novel missense variations, p.Thr300Met (c.899C>T) and p.Glu638Lys (c.1912G>A) within LARS2, encoding the mitochondrial leucyl-tRNA synthetase,. The segregation of the two mutations in the pedigree is compatible with the autosomal recessive inheritance of the disease. Both Thr300 and Glu638 residues are evolutionary conserved, and are respectively located within the editing domain and immediately before the KMSKS sequence, a unique signature of the catalytic domain of class 1 aminoacyl-tRNA synthetases. The identified mutations were confirmed to be absent in an in-house database of about 3500 ethnically-matched control exomes. Apart from the original report in 2013, to our knowledge, this is the first study confirming the role of LARS2 mutations in PRLTS pathogenesis. This study was supported by: Italian Telethon Foundation (grant#GGP11177) and Fondazione Cariplo, grant N°2013-0825.