Identification of novel deafness-causing variants in the tmprss3 gene by whole-exome sequencing

Whole-exome next-generation sequencing (WES) currently represents one of the most efficient strategies to identify causative mutations underlying highly heterogeneous inherited diseases, such as nonsyndromic sensorineural hearing loss (NSHL). In this study, three NSHL families (NSHL6-8), with a recessive inheritance pattern and at least two affected individuals, were subjected to WES using the 50M SureSelect exome capture enrichment kit (Agilent) and an HiSeq 2000 sequencer (Illumina). All the analyzed probands were negative for variations in the GJB2, GJB6, and MTRNR1 genes. For two families (NSHL7 and 8), no putative pathogenic mutations in known NSHL genes were found. Candidate variants in novel genes are currently being tested to evaluate their segregation with the disease in the probands’ families and their recurrence in a cohort of 1124 Italian NSHL patients. In the third analyzed family (NSHL6), instead, two novel variants (Trp268Arg and Arg435His) in the TMPRSS3 gene (transmembrane serine protease 3, DFNB8/10 locus) were found in the heterozygous state and shown to segregate with post-lingual, bilateral, high-frequency hearing loss. Both missense mutations are located within the serine-protease domain of TMPRSS3 and affect evolutionarily conserved amino acids. Although several NSHL-causing mutations in TMPRSS3 have been described over the years, the actual function of this protein in the auditory system is currently elusive. The existence of at least one hortologue in zebrafish (Danio rerio) with a sequence identity of about 56% with the human protein, suggests the use of this model to better understand the role of TMPRSS3 in hair-cell development, as well as the impact of the identified mutations on the protein function. In conclusion, we provide evidence of the usefulness of WES for the genetic diagnosis of NSHL and we contribute to amplify the mutational spectrum of the TMPRRS3 gene.