Inherited nonsyndromic sensorineural hearing loss (NSHL) is characterized by a high level of genetic heterogeneity, making extremely challenging to obtain a molecular diagnosis with traditional screening methods. Whole exome sequencing (WES) has been recently introduced as an alternative approach to search for alleles underlying Mendelian disorders and has been successfully applied for gene/mutation discovery. In this study, we used WES to identify the pathogenic mutations responsible for NSHL in three families (NSHL6, 11, and 12), with a recessive inheritance pattern and at least two affected siblings. A total of 9 individuals were subjected to WES using the SeqCapEZ Exome capture kit (Roche) and the HiSeq 2000 sequencer (Illumina). In particular, the NSHL6 patients were compound heterozygous for two novel mutations within the TMPRSS3 gene (DFNB8/10 locus). Both variants segregate with post-lingual, bilateral, high-frequency NSHL and affect evolutionary conserved amino acids located within the TMPRSS3 catalytic domain. In the NSHL11 family, two novel missense variants were found in the heterozygous state in OTOGL, a gene that was only recently associated with NSHL (otogelin-like protein, DFNB84 locus). Finally, in the consanguineous NSHL12 pedigree, WES coupled with homozygosity mapping analysis pointed out a known missense variant (rs74315438) in the CLDN14 (DFNB29 locus) gene, coding for the claudin 14 protein. In conclusion, we provide evidence of the usefulness of WES for the diagnosis of NSHL and increase the knowledge on the genetic defects underlying this disease. This study was supported by: Italian Telethon Foundation (grant#GGP11177) and Fondazione Cariplo, grant N°2013-0825.
Identification of novel NSHL-causing mutations by whole exome sequencing / M. Robusto, C. Chiereghin, R. Asselta, P. Castorina, S. Caccia, E. Benzoni, M. Seia, U. Ambrosetti, S. Duga, G. Soldà. ((Intervento presentato al convegno European Human Genetics Conference (ESHG) tenutosi a Milano nel 2014.
|Titolo:||Identification of novel NSHL-causing mutations by whole exome sequencing|
ROBUSTO, MICHELA (Primo)
|Data di pubblicazione:||giu-2014|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore MED/32 - Audiologia
Settore BIO/13 - Biologia Applicata
|Citazione:||Identification of novel NSHL-causing mutations by whole exome sequencing / M. Robusto, C. Chiereghin, R. Asselta, P. Castorina, S. Caccia, E. Benzoni, M. Seia, U. Ambrosetti, S. Duga, G. Soldà. ((Intervento presentato al convegno European Human Genetics Conference (ESHG) tenutosi a Milano nel 2014.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|