Identification by exome capture and sequencing of two novel mutations in the PRPS1 gene in Italian families with nonsyndromic sensorineural hearing loss

The high genetic and allelic heterogeneity of nonsyndromic sensorineural hearing loss (NSHL) makes extremely challenging to obtain a definitive genetic diagnosis in most patients, since genetic screening of all known NSHL-causing genes by traditional 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 successfully applied to the discovery of novel genes responsible for autosomal and X-linked recessive NSHL. In this study, we selected for exome sequencing four NSHL families (NSHL1-4), with a recessive inheritance pattern and at least two affected individuals. All probands were negative for mutations in the GJB2, GJB6, and MTRNR1 genes. Genomic capture with the SureSelect 38M exome kit (Agilent), data processing and first bioinformatics analyses were performed through a collaboration with BGI (Beijing Genomics Institute), in the frame of the “1000 Mendelian disease project”. Putative pathogenic mutations pointed out by NGS 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 proband of family NSHL4, a novel missense mutation within PRPS1, a gene already involved in both nonsyndromic (DFN2) and syndromic (PRPS1 superactivity, Arts syndrome, Charcot-Marie Tooth 5) forms of X-linked recessive sensorineural deafness, was found. The identified mutation segregates with prelingual, bilateral, profound NSHL in the proband’s family. The subsequent screening of all PRPS1 exons in 13 unrelated male probands with familiarity for NSHL, and a likely X-linked inheritance pattern, led to the discovery of a second novel mutation segregating with pre-lingual hearing impairment. The functional impact of both mutations is currently under analysis by measuring the enzymatic activity of phospho-ribosylpyrophosphate synthetase 1 (the protein product of PRPS1) in the patients’ blood. In conclusion, we provide further evidence of the usefulness of whole-exome NGS for the genetic diagnosis of NSHL and we highlight the recurrence of PRPS1 mutations in Italian patients with X-linked NSHL.