Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

Journal of Human Genetics (2010) 55, 639–648 & 2010 The Japan Society of Human Genetics All rights reserved 1434-5161/10 $32.00 www.nature.com/jhg REVIEW Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations Nejat Mahdieh1, Bahareh Rabbani2, Susan Wiley3, Mohammad Taghi Akbari1 and Sirous Zeinali4,5 Hearing loss (HL) is the most prevalent sensory defect affecting 1 in 500 neonates. Genetic factors are involved in half of the cases. The extreme heterogeneity of HL makes it difficult to analyze and determine the accurate genetic causes of the impairment. Up to now, 10 genes, namely, GJB2, GJB6, SLC26A4, TECTA, PJVK, Col11A2, Myo15A, TMC1, RDX and microRNA (miR-183), have been studied in an Iranian population. The prevalence of HL in Iran was estimated to be 2–3 times higher than that in other parts of the world. Here, the most common bases of congenital nonsyndromic hearing loss (NSHL) are discussed. We reviewed GJB2, GJB6 (large deletion), TECTA, SLC26A4 and PEJVK mutations, and studied their frequencies and distributions in different ethnic groups in 1934, 500, 121, 80 and 34 unrelated families throughout Iran, respectively. GJB2 mutation was the most common factor causing NSHL, with a mean frequency of 18.17% in the Iranian population. The importance of Iran’s geographical location in the migration pathway from west to east through the silk route was also highlighted. SLC26A4 and TECTA mutations were the second and third main reasons of HL and accounted for up to 10 and 4% of prelingual HL in Iran, respectively. Mutations in GJB2, SLC26, TECTA and PJVK genes have an important role in HL in Iran and a screening test should be generated for better intervention and diagnosis programs. Journal of Human Genetics (2010) 55, 639–648; doi:10.1038/jhg.2010.96; published online 26 August 2010 Keywords: genetic diagnosis; GJB2; Iranian population; mutations; nonsyndromic hearing loss; SLC26A4; TECTA INTRODUCTION Hearing loss (HL) is a complex disorder and accounts for 1.86 of 1000 newborns worldwide. The frequency of the disorder increases by age, that is, it affects 2.7 of 1000 before the age of 5 years and 3.5 of 1000 in adolescents.1 Many environmental factors, such as drug exposure, bacterial or viral infections and trauma, can cause HL; however, a significant proportion of cases is due to genetic factors. Different criteria are applied for the classification of HL (Table 1). Considering clinical phenotypes, nonsyndromic hearing loss (NSHL) is responsible for nearly two-third of hereditary congenital cases and the remaining accounts for syndromic forms of HL. The only impairment in the former group is HL, whereas HL is a part of broader clinical symptoms in the syndromic form. The cochlea is an important part of the inner ear, containing the organ of Corti. Sound vibrations are converted into electrobiochemical impulses in this organ and sent to the brain through the auditory nerve. Numerous genes have been described to be expressed in this pathway, including genes encoding cytoskeleton proteins, gap junction channels, membrane transport proteins, ion channels, regulatory elements and microRNAs (miRNAs).2–4 Monogenic inheritance (NSHL) is responsible for 70% of all congenital HL. All Mendelian inheritance patterns have been observed for prelingual HL. Different distributions of each pattern have been delineated in many studies: autosomal recessive (DFNB loci) in 80%, autosomal dominant (DFNA loci) in 20%, X-linked (DFN loci) in 1% and mitochondrial inheritance in 1% of cases.2–7 Thus, autosomal recessive NSHL (ARNSHL) has a high prevalence among these patterns of inheritance. In traditional communities such as the Middle East, consanguineous or intragroup marriages may even increase the proportion of ARNSHL among all forms of HL. More than 80 loci have been identified for ARNSHL, of which a significant percentage is attributed to mutations in the DFNB1 locus (especially GJB2 mutations) in Caucasians. Iran’s population is B75 million, with HL affecting an estimated 450 000 individuals.8 In other words, 1 in 166 individuals is affected. Accurate genetic counseling is desired for early intervention of lateonset forms. Significant amounts of health-care expenditures are targeted for its maintenance each year in Iran; hence, preliminary molecular diagnosis would help to reduce the socioeconomical and mental disturbances of the affected individuals and their families. HL encompasses a broad field of research, including understanding mechanisms underlying the disease, genes involved in different pathways, gene therapy (as a new treatment modality) and molecular diagnosis, for example, preimplantation genetic diagnosis. Considerable assistance in care is achieved through collection of mutations for diagnostic laboratories, clinicians and researchers.9 Recently, the 1Department of Medical Genetics, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran; 2Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran; 3Division of Developmental and Behavioral Pediatrics, Division of Pediatric Otolaryngology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA; 4Kawsar’s Human Genetic Research Center, Tehran, Iran and 5Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran Correspondence: Dr N Mahdieh, Department of Medical Genetics, Faculty of Medicine, Tarbiat Modares University, Jalal-Al-Ahmad Avenue, Tehran 14115-331, Iran. E-mail: Received 21 June 2010; revised 10 July 2010; accepted 13 July 2010; published online 26 August 2010 Genetic causes of NSHL in Iran N Mahdieh et al 640 Table 1 Various criteria for the classification of hearing loss Criterion Class Definition and example Etiology Environmental (acquired) Caused by acquired agents such as viral and bacterial infection (prenatal, for example, CMV, toxoplasmosis, rubella; postnatal, for example, meningitis), hyperbilirubinemia, head trauma, anoxia, noise exposure Age onset Clinical Genetic and ototoxic drugs Caused by mutations in nuclear and Idiopathic mitochondrial genes Unexplained hearing loss Prelingual hearing loss Postlingual hearing loss Hearing loss occurs after the onset of speech Presbycusis Syndromic Age-related hearing loss Deafness is associated with other Nonsyndromic phenotypes Deafness is the only defect Conductive hearing loss Caused by a problem conducting phenotypes Place of defect Severity Inheritance Hearing loss occurs before language has been acquired sound waves through the outer ear, tympanic membrane or middle ear Table 2 Studied genes involved in congenital hearing loss in Iranian population No. of exons families families GJB2 13q11–12 2 1934 387 (DFNB1) and Mahdieh et al.27 GJB6 6 4500 0 Najmabadi et al.,24 Bonyadi et al.26 and Mahdieh et al.27 TECTA 11q22–24 23 75 1 Alasti et al.78 (DFNB21) SLC26A4 45 3 77 1 1 (...truncated)