Whole Exome Sequencing in Hereditary Hearing Loss patients in Argentina: step by step to the success.

BRUQUE CARLOS DAVID; MENAZZI SEBASTIAN; DALAMÓN VIVIANA KARINA; BUONFIGLIO PAULA; GOLDSCHMIDT E; ANA BELEN ELGOYHEN; LOTERSZTEIN VANESA; BIBIANA PAOLI

Congreso; European Human Genetics Virtual Conference; 2020

Sociedad Europea de Genetica Humana

Hereditary hearing loss is the most common sensory disorder that affects 1:500 new born children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity leads us to design a diagnosis multistep strategy to analyze patients by Whole Exome Sequencing Technique (WES).Our objective was to diagnose Argentinean deaf families as well as analyzing novel genetic variations or new genes identified, related to hearing impairment.After excluding GJB2 and GJB6 frequent mutations, by Sanger Sequencing, WES technique was performed. Filtering process was applied in order to collect presumably 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. 28 families with syndromic and non-syndromic hearing loss were selected to be studied by WES. 16/28 patients 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. We showcased in the present study clear-cut results using WES analysis as a successful strategy for hearing loss genetic diagnosis. Our algorithm is advantageous and valuable for large-scale molecular analysis. These findings clearly highlight the importance of genetic studies followed by in-sílico and in-vivo validation to better understand the genetic basis of Hereditary Hearing loss.