NONSYNDROMIC HEARING LOSS IN QATAR: THE GENETIC BASIS AND THE DIAGNOSTIC YIELD OF GENETIC TESTING

Abstract

Background: Hearing loss is the most predominant sensory defect worldwide with around 8% of cases occurring in children. Approximately 66% of childhood-onset hearing loss cases are attributed to genetic factors. The prevalence of hereditary hearing loss increases in consanguineous populations, and the prevalence of hearing loss in Qatar is 5.2%. Aim: We aim to investigate the genetic basis of nonsyndromic hearing loss (NSHL) in Qatar and evaluate the diagnostic yield of different genetic tests, including GJB2 gene sequencing, chromosomal microarray, gene panel, whole exome sequencing, and mitochondrial genome sequencing and deletion testing. Methodology: A retrospective chart review was conducted for 128 eligible pediatric patients with NSHL referred to the Clinical and Metabolic Genetics department at Hamad Medical Corporation between 2014 and 2019, and who underwent at least one genetic test. Results: Our study revealed an overall diagnostic yield of 30.5%, attributed to 19 variants in 11 genes and two copy number variants. 36.8% of the causative variants were identified in GJB2 gene, with the most common was c.35delG as it was seen in 9 out of 39 cases (23.1%) genetically diagnosed patients. We identified the known Qatari founder c.506G>A in GJB2 gene in our cohort. Additionally, c.283C>T in FGF3 gene was associated with NSHL for the first time worldwide. The reassessment of variants of unknown significance (VUS) resulted in identifying eight variants as being likely contributing to NSHL in our cohort, including c.3641G>A in MYO15A, c.6503T>G in MYO15A, c.599C>T in WHRN, c.2476G<A and c.4696A>T in MYO7A, c.-182G>A and c.617-3_617-2dup in TMPRSS3, and c.98G>A in OTOF. Moreover, GJB2 gene sequencing and gene panel testing were the two tests significantly associated with positive diagnostic yield. Conclusion: Our work adds new insight into the genetic basis of NSHL in Qatar. Based on our findings, we recommend performing GJB2 gene sequencing as a first-tier genetic test for NSHL and gene panel as a second-tier genetic test for NSHL. We also encourage clinicians to consider reassessing VUS based on ACMG guidelines.