RESEARCH ARTICLE A Comprehensive Study to Determine Heterogeneity of Autosomal Recessive Nonsyndromic Hearing Loss in Iran Mojgan Babanejad, 1 Zohreh Fattahi, 1 Niloofar Bazazzadegan, 1 Carla Nishimura, 2 Nicole Meyer, 2 Nooshin Nikzat, 1 Elahe Sohrabi, 1 Amin Najmabadi, 1 Peyman Jamali, 3 Farkhonde Habibi, 4 Richard J.H. Smith, 2 Kimia Kahrizi, 1 and Hossein Najmabadi 1 * 1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran 2 Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology Head and Neck Surgery, University of Iowa, Iowa 3 Shahrood Welfare Organization, Shahrood, Iran 4 Rasht Welfare Organization, Rasht, Iran Manuscript Received: 14 June 2012; Manuscript Accepted: 23 June 2012 Hearing loss is the most common sensory disorder worldwide and affects 1 of every 500 newborns. In developed countries, at least 50% of cases are genetic, most often resulting in non- syndromic deafness (70%), which is usually autosomal recessive (80%). Although the cause of hearing loss is heterogeneous, mutations in GJB2 gene at DFNB1 locus are the major cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) in many populations. Our previous study showed that mutations of GJB2 gene do not contribute to the major genetic load of deafness in the Iranian population (16%). Therefore, to define the importance of other genes in contributing to an ARNSHL phenotype in the Iranian population, we used homozygosity mapping to identify regions of autozygosity-by-descent in 144 families which two or more progeny had ARNSHL but were negative for GJB2 gene mutations. Using flanking or intragenic short-tandem repeat markers for 33 loci we identified 33 differ- ent homozygous variations in 10 genes, of which 9 are novel. In aggregate, these data explain 40% of genetic background of ARNHSL in the Iranian population. Ó 2012 Wiley Periodicals, Inc. Key words: autosomal recessive nonsyndromic hearing loss; mutation detection; homozygosity mapping; Iran INTRODUCTION Hearing loss is one of the most common sensorineural deficits in humans, affecting more than 350 million people in developed countries. The incidence of profound hearing loss (HL) is estimated about 1–2 per 1,000 newborns in these countries. HL can be due to environmental factors, genetic etiologies, or both. At least 50% of pre-lingual HL is estimated to be caused by genetic changes with more than 70% of genetic HL being nonsyndromic, and most frequently autosomal recessive (80%) [Morton, 1991; Cohen and Gorlin, 1995; Cryns and van Camp, 2004]. Monogenic HL is extremely heterogeneous with over 150 mapped loci and 60 causally implicated genes (http://www.hereditaryhearingloss.org). Despite such heterogeneity, GJB2 (OMIM#121011) mutations are the most frequent cause of ARNSHL in most world populations and in some countries account for more than 50% of the ARNSHL genetic load [Zelante et al., 1997; Kenneson et al., 2002]. In Iran, HL is second to intellectual disability as the most common disability, affecting 1 of every 166 persons [Mahdieh et al., 2010]. Due to a high percentage of consanguineous marriages [Saadat et al., 2004], autosomal recessive disorders are more common than in many other populations and HL is no exception. Several studies have demonstrated that the contribution of GJB2 gene mutations to ARNSHL in Iran is about 16% [Najmabadi et al., *Correspondence to: Hossein Najmabadi, Ph.D., Professor of Medical and Molecular Genetics, Head and Director of the Genetic Research Center, Director of National Prenatal Reference Laboratory, University of Social Welfare and Rehabilitation Sciences, Koodakyar Street, Daneshjoo Blvd., Evin, Tehran 1985713834, Iran. E-mail: hnajm12@yahoo.com Article first published online in Wiley Online Library (wileyonlinelibrary.com): DOI 10.1002/ajmg.a.35572 How to Cite this Article: Babanejad M, Fattahi Z, Bazazzadegan N, Nishimura C, Meyer N, Nikzat N, Sohrabi E, Najmabadi A, Jamali P, Habibi F, Smith RJH, Kahrizi K, Najmabadi H. 2012. A comprehensive study to determine heterogeneity of autosomal recessive nonsyndromic hearing loss in Iran. Am J Med Genet Part A. Ó 2012 Wiley Periodicals, Inc. 1