whole exome sequencing in hereditary hearing loss in argentinean patients

BUONFIGLIO PAULA; BRUQUE CARLOS DAVID; VANESA LOTERSZTEIN; GOLDSCHMIDT E; ANA BELEN ELGOYHEN; DALAMÓN, VIVIANA KARINA

Ciudad Autonoma de Buenos Aires

Congreso; Second International Hearing research symposium- IHear Closing the Auditory Eferent loop IV; 2019

Hereditary hearing loss is the most common sensory disorder that affects 1:500 newborn children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity led us to design a multistep diagnosis strategy with the use of Whole Exome Sequencing Technique (WES). The main objectives were molecular diagnosis of deaf patients and novel genetic variants analysis.After excluding GJB2 and GJB6 frequent mutations by Sanger Sequencing, WES technique was performed. A filtering process was applied in order to collect probable pathogenic mutations, ruling out spurious variations. Identified mutations were studied via bioinformatic analysis. Additionally, conservation studies along with structure and functional protein domain analysis and in-vivo validation were carried out. Approximately 25% of 1250 patients were diagnosed by GJB2/GJB6 analysis. A total of 28 families with syndromic and non-syndromic hearing loss were selected to study by WES. Out of the 28 families, 16 were diagnosed (57%), identifying 23 causative mutations (11 were novel and 12 previously reported). Mutation functional impact analysis with Bioinformatic Tools revealed that identified mutations were damaging to the proteins. Functional in vivo analysis using Zebra fish models are under way. In the present study we showcase clear-cut results using WES analysis as a successful strategy for the genetic diagnosis of hearing loss. Our algorithm is advantageous and valuable for large-scale molecular analysis. These findings clearly highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of hereditary hearing loss.