Search for novel deafness genes by exome sequencing of autosomal recessive NSHL families

Due to the extremely high genetic heterogeneity of non-syndromic sensorineural hearing loss (NSHL), as well as to the low frequency of most known NSHL-causing mutations, the vast majority of NSHL patients have no definitive genetic diagnosis. In addition, targeted genetic screening of all known NSHL-causing genes by traditional mutation analysis methods is unfeasible. Instead, whole-exome next generation sequencing (NGS) currently represents the most promising and efficient strategy to search for rare variants underlying Mendelian diseases, and has already been applied to the discovery of a novel gene/mutation responsible for autosomal recessive NSHL (DFNB82 locus). In this study, we selected for exome sequencing five NSHL families, with a clear autosomal recessive inheritance pattern and at least two affected individuals. All probands resulted negative for mutations in the GJB2, GJB6 and mitochondrial MTRNR1 genes. Three families show no consanguinity and prelingual, bilateral, profound NSHL, whereas the remaining two show consanguinity and post-lingual onset of the hearing impairment. Genomic capture, NGS, basic data processing and first bioinformatics analysis have been performed through a collaboration with BGI (Beijing Genomics Institute), in the frame of the “1000 Mendelian diseases” project. Putative pathogenic mutations identified by exome sequencing will first be tested to evaluate their segregation with the disease within the probands’ families and their recurrence in sporadic and familial NSHL cases. In this frame, the availability of a large non-syndromic deafness series (1124) of patients/families will be a key resource in the validation step, to screen for the identified mutations and to search for additional genetic defects in the candidate genes pointed out by whole-exome sequencing.