?WHOLE EXOME SEQUENCING FOR GENETIC DIAGNOSIS OF HEARING LOSS

BUONFIGLIO PAULA; ANA BELEN ELGOYHEN; BRUQUE CARLOS DAVID; DALAMÓN, VIVIANA KARINA

Caxias do Sul

Workshop; Escuela Latino-Americana de Genética Humana y Médica - ELAG; 2018

Hereditary Hearing Loss (HHL) is a common trait affecting 1 in 2000 new born children. The presence of over 150 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 present in this work 6 families that were analyzed by WES techniques (3 syndromic and 3 non-syndromic cases). We identified 9 causative mutations in 5 families (5 missense, 2 frameshift, 1 non-sense and 1 splicing site mutations). Six were novel and functional studies of some of the identified mutations, using Zebra fish models, are under way. 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.