Unraveling the Genetic Landscape of Congenital Hearing Loss in Lebanon

Abstract

Hearing impairment is the most prevalent sensory disorder, affecting approximately 1 in 500 newborns worldwide, with genetic factors accounting for nearly 50% of cases. In regions like the Middle East, including Lebanon, consanguineous marriages significantly contribute to a higher prevalence of autosomal recessive forms of congenital hearing loss (CHL). Despite substantial advances in identifying deafness causing genes, exceeding 100 loci, knowledge gaps remain, particularly concerning population-specific genetic variations and atypical clinical presentations. This research aims to elucidate the genetic basis of CHL among the Lebanese population by investigating the specific genetic mutations associated with different presentations, including typical and atypical CHL. We hypothesize that the high rate of consanguinity in Lebanon has led to the enrichment of specific autosomal recessive deafness-causing mutations, some of which may be novel, contributing to the genetic heterogeneity of CHL in the Lebanese population. Utilizing Whole Exome Sequencing (WES) data from affected families, we performed comprehensive bioinformatic analyses to identify candidate deafness-causing mutations. To confirm pathogenicity, the most promising variants were validated through Sanger sequencing in affected individuals and their unaffected family members. A phylogenetic analysis of pedigrees was also conducted to explore these mutations' inheritance patterns and evolutionary implications. Understanding the genetic mutations prevalent in Lebanon holds significant value. It enables the development of tailored genetic tests for earlier and definitive CHL diagnoses, facilitates informed genetic counseling for affected families, and informs public health initiatives such as carrier and newborn hearing screening programs. This study can potentially uncover novel mutations responsible for CHL in Lebanon, bridging critical knowledge gaps and contributing to improved diagnostic and preventive strategies for hereditary hearing loss.