In a brother and sister, born of unrelated Italian parents, with Perrault syndrome-4 (PRLTS4; 615300), Solda et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene: a c.899C-T transition (c.899C-T, NM_015340.3), resulting in a thr300-to-met (T300M) substitution in the editing domain, and a c.1912G-A transition, resulting in a glu638-to-lys (E638K; 604655.0005) substitution in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Sequencing Project databases, and segregated with the disorder in the family. The mutations were not found in the ExAC database or in an in-house database of 3,500 ethnically matched controls. The E638 residue is highly conserved, whereas the T300 residue is conserved in mammals, but not in more distantly related species. Molecular modeling based on the E. coli structure suggested that both mutations would be deleterious. In vitro functional studies and studies on patient cells were not performed.
