Genetic Variant Curation in GJB2 and GJB6 genes from an Argentinean cohort of hearing loss patients.

BUONFIGLIO PAULA; BRUQUE CARLOS DAVID; MENAZZI, SEBASTIÁN; FRANCIPANE, LILIANA; LOTERSZTEIN, VANESA; ANA BELEN ELGOYHEN; DALAMÓN, VIVIANA KARINA

Modalidad Virtual

Congreso; European Human Genetics Virtual Conference 2021; 2021

European Society of Human Genetics

Hereditary hearing impairment affects 1-500 newborn children. It is characterized by the large amount of genes involved (more than 100) and its phenotype heterogeneity. Despite the wide genetic variety of hearing impairment, the most commonly mutated genes in severe to profound autosomal recessive non-syndromic hearing loss are GJB2 and GJB6, accounting for nearly 50% of the cases in most populations around the Mediterranean Sea. Molecular diagnosis enables proper genetic counseling and medical prognosis to patients. Therefore, correct interpretation of the phenotypic consequences of genetic variants is crucial in genetic diagnosis, since discrepancies in sequence variant interpretation and classification has been reported to lead to serious impact in patient health maintenance.In this study we aimed to identify the genetic causes of hearing loss and performed a manual genetic variant curation following the American College of Medical Genetics and Genomics/Association for Molecular Pathology ACMG/AMP standards and hearing-loss-gene-specific criteria of the ClinGen Hearing Loss Expert Panel.A total of 600 patients were studied for genetic variants in GJB2 and GJB6 genes by Sanger Sequencing technique and Multiplex Gap-PCR, respectively.Overall, 48 different sequence variants were detected in our cohort of patients, being the c.35delG the most common causative variant identified. Besides, more than 50% of sequence variants were reclassified from their previous categorization in ClinVar after careful manual analysis. These results provide an accurately analysed and interpreted set of variants to be taken into account by clinicians and the scientific community, and hence, aid the precise genetic counseling to patients.