Lessons Learnt from Genetic Studies of Autosomal Recessive Non-Syndromic Hearing Loss: Implications for Molecular Diagnostics in Iran

Hearing loss (HL) is the most frequent sensory birth defect in human. Autosomal recessive non-syndromic HL (ARNSHL) is the most common type of hereditary HL. Iran, with a high rate of consanguinity has a much higher rate of ARNSHL than expected. Its extreme genetic heterogeneity, with Over 70 known loci is still a big challenge for molecular diagnostics Methods: over 250 Iranian multiplex families from several provinces which were negative for GJB2, as the most common cause of HL, were recruited. They were screened for up to 15 DFNB loci using genetic linkage analysis. In a subset of the remaining families, next-generation sequencing (NGS) and genome-wide homozygosity mapping were performed, Necessary steps such as Sanger sequencing and co-segregation studies were followed Results: GJB2 is the first gene to be investigated in ARNSHL (16% in average) followed by mutations in SLC26A4 (DFNB4) (8-10%). Although a variety of other loci are involve in the rest of cases, 6 -7 of them are among the ones that are worth being screened including DFNB2 (MYO7A), DFNB3 (MYO15A), DFNB21 (TECTA), DFNB7/11(TMC1), DFNB9 (OTOF) and DFNB24 (RDX). NGS is very promising in clarification of the etiology and pathogenic variants in several rare genes as well as novel genes have been identified. To minimize costs, it would be logical to define a panel of genes for Iran. Conclusion: Advancement in technologies combined with population-specific profiles of genes could set the stage for genetic diagnostics of HL.

Keywords:

molecular diagnosis , deafness , genetic linkage analysis , Next-generation sequencing , Iran