Large-scale molecular study of hereditary hearing loss genes in deaf patients: wide range of possibilities

ELGOYHEN AB; BUONFIGLIO P; DALAMÓN V; BRUQUE CD; LOTERSZTEIN V

Congreso; LXII Sociedad Argentina de Investigación Clínica; 2017

?LARGE-SCALE MOLECULAR STUDY OF HEREDITARY HEARING LOSS GENES IN DEAF PATIENTS: WIDE RANGE OF POSSIBILITIES?Hereditary Hearing Loss (HHL) is a common trait affecting 1 in 2000 new born children. The genotype heterogeinity and 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 a putative correlation between hearing loss and sequence variations.We designed a flowchart in order to exclude all the probably spurious variations obtained and target for few candidates. To approach this, we filtered results and candidate variations were segregated throughout family members looking for relationship with phenotype. Variations positively selected, were analyzed using different bioinformatics predictors in order to study amino acid change impact in proteins and looking for pathogenicity. Additionally, conservation studies, structure and functional domain analysis in proteins, collection of information from databases, prediction of functionality and functional analysis in vivo were performed.Using this strategy we identified causative mutations in four families with syndromic and non-syndromic hearing loss. Analysis and filtering process of more than 100 genes were successful and we identified two missense variants that had been previously reported, and two missense and frameshift mutations that resulted novel. In one family no causative mutations were identified in the 100 candidate genes so a Trio WES analysis is still in process in order to propose a new candidate gene possibly related to the pathology.Functional studies of some of the identified mutations, using Zebra fish models, are under way.We show in the present study some clearcut results using WES analysis as a successful strategy for hearing loss study. We prove that our flowchart is advantageous and noteworthy for large-scale molecular analysis. These findings clearly highlight the importance of genetic studies followed byin sílico and in-vivo validation to better understand the genetic basis of Hereditary Hearing loss.Keywords: Hearing loss; mutations, whole exome sequencing, filtering process, functional studies.