Large-Scale Molecular Study of Hereditary Hearing Loss genes in deaf patients: range of possibilities

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

Milan

Congreso; European Human Genetics Conference 2018; 2018

European Society of Human Genetics with the European Meeting on Phychosocial Aspects of genetics

Hereditary Hearing Loss (HHL) is a common trait affecting 1 in 2000 new born children. The presence of over 100 different genes involved in HHL, lead us to go on board with Whole Exome Sequencing (WES) in order to search for the causative mutations.The main objective of this project was to diagnose Argentinean deaf families and discover novel mutations or new genes involved in pathology.We designed a flowchart to exclude all the spurious variations obtained and target for few candidates. To approach this, we filtered results, and candidate variations were segregated throughout family members. Variations positively selected, were analyzed using bioinformatic predictors and tracked in public databases. Additionally, conservation studies, structure and functional domain analysis in proteins, and in-vivo studies were performed.Using this strategy we analysed 15 WES results. We identified 16 causative mutations in 12 families with syndromic and non-syndromic hearing loss (11 missense, 4 frameshift and 1 splicing site mutations). Six were novel and functional studies of some of the identified mutations, using Zebra fish models, are under way. In the remaining 3 families, variables of uncertain significance were detected (Vous).To our knowledge this is the first study using WES to diagnose deaf patients in Argentina. We show in the present study that our flowchart is advantageous and noteworthy for large-scale molecular analysis in deaf patients. 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.