fifteen years investigation to elucidate the genetic heterogeneity of hearing loss in iranian population

hearing loss (hl) is the most common communication disorder affecting about 1/1000 births worldwide caused by environmental or genetic factors. about 30-50% is attributed to genetic factors and till now more than 85 genes have been implicated in non-syndromic hl. in iran, hl is second to intellectual disability as the most common disability, affecting 1 of every 166 persons. about 15 years ago the studies of genes causing deafness have been started in genetics research center (grc) of university of social welfare and rehabilitation sciences, tehran, iran. over 2500 families with hereditary hl have been referred to grc from different parts of iran. almost all families have been investigated for the frequency of gjb2 gene mutations.the mutation in this gene is the most prevalent gene causing hereditary hl (hhl) in iran. total of 395 families had gjb2 gene mutations. the prevalence of gjb2-related deafness is relatively low in our country comparison with north american and european countries. we have also determined the prevalence of other known genes in our heterogeneous population. in order to determine iranian ar hereditary hl gene spectrum we used a custom targeted genomic enrichment panel which included all the 116 known hhl genes. a total of 302 gjb2-negative families were selected to be studied using targeted ngs panel. we established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: slc26a4, myo15a, myo7a, cdh23 and pcdh15. taken together, it can be concluded that the overall diagnosis rate of hhl in iran is about 83%. the families which failed to identify plausible disease-causing variants using targeted ngs are a valuable cohort for novel deafness-gene discovery. among them 23 families have been subjected to whole exome sequencing till now for whom we have identified 7 novel genes so far. in conclusion it should be mentioned that we have identify over 83% of hereditary hearing loss genes in iranian population and we have already identify number of candidate genes for the remaining 17% of the families.