richard j. h. smith

Diagnosis of hereditary hearing loss (HHL) as a heterogeneous disorder is very important especially in countries with high rates of consanguinity where the autosomal recessive pattern of inheritance is prevalent. Techniques such as next-generation sequencing, a comprehensive genetic test using targeted genomic enrichment and massively parallel sequencing (TGE + MPS), have made the diagnosis more cost-effective. The aim of this study was to determine HHL variants with comprehensive genetic testing in our country.

  Fifty GJB2 negative individuals with HHL were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, one of the reference diagnostic genetic laboratories in Iran, during a 3-year period between 2014 and 2017. They were screened with the OtoSCOPE test, the targeted genomic enrichment and massively parallel sequencing (TGE + MPS) platform after a detailed history had been taken along with clinical evaluation.

Among 32 out of 50 GJB2 negative patients (64%), 34 known pathogenic and novel variants were detected of which 16 (47%) were novel, identified in 10 genes of which the most prevalent were CDH23, MYO7A and MYO15A.

These results provide a foundation from which to make appropriate recommendations for the use of comprehensive genetic testing in the evaluation of Iranian patients with hereditary hearing loss.

A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment.

Hearing loss is the most common sensory neural defect in humans, affecting 1 in 1000 neonates, with over half of these cases predicted to be hereditary in nature. Most hereditary hearing loss is inherited in a recessive fashion, accounting for approximately 80 % of non-syndromic hearing loss (NSHL). Mutations in GJB2 gene are major cause of inherited deafness in the European and American populations. To date, more than 90 mutations have been reported in this gene. Although most of these mutations are rare but 35delG mutation is the most common deafness causing allelic variant of GJB2 in most parts of the world.

In this project, 120 probands from 120 families with ARNSHL in Yazd Province were studied. Mutations Screening of GJB2 was performed by Amplification Refractory Mutation System (ARMS)-PCR for detection of 35delG and then all samples excluding 35delG homozygote were analyzed by DHPLC and Direct Sequencing.

GJB2-related deafness was present in 7.5% of this population. We identified 4 mutations (35delG, 312del14, 314del14 and 167delT) and 4 polymorphisms (V153I, V27I, E114G and R127H) in this study.

Prevalence of GJB2 mutations in this population was lower than American and European populations, and also other provinces of Iran. Interestingly, 312del14 rather than 35delG was the most common mutation found in the population under study. 56.25 % of GJB2 mutant alleles carried 312del14 mutation. To date, this frequency has not been reported in any of the world populations.