Expanding the Mutation Spectrum of Autosomal Recessive Non-Syndromic Hearing Loss in the Iranian Families

Hearing loss is known as the most common sensory disorder in humans, with an incidence of 466 million people worldwide. This disorder is genetically highly heterogeneous, so among the 180 genes responsible for hearing loss, a disproportionate share of genes is involved in different ethnicities. Here, we report the underlying genetic cause of non-syndromic hearing loss segregating in four unrelated Iranian families. In the first step, patients were examined for mutations in the common genes GJB2 and GJB6. After confirming the negativity of mutations in these genes, the affected patients were subjected to targeted-exome sequencing. Subsequently, Sanger sequencing was used to confirm the mutations found in the patients and their family members. In-silico analyses were used to consider the possible deleterious effect of the identified variants on encoded proteins. Targeted-exome sequencing revealed a novel intronic mutation c.490-8C>A in the CABP2 gene, a novel ~154 kb deletion mutation including the OTOA gene involved in hearing loss, and two previously reported mutations: a pathogenic/likely pathogenic variant c.413C>A in the TMPRSS3 gene and a c.966dupC variant with conflicting classifications of pathogenicity in the COL11A2 gene. However, the audiological evaluations, segregation analysis, and in-silico approaches confirmed the disease-causing nature of all mutations found. Our findings could extend the pathogenic mutation spectrum of non-syndromic hearing loss, highlight the high genetic heterogeneity of hearing loss, and also aid in conducting genetic counseling, prenatal diagnosis, and clinical management of hearing loss in the Iranian population.