Christina M Sloan-Heggen1, Mojgan Babanejad2, Maryam Beheshtian2, Allen C Simpson3, Kevin T Booth3, Fariba Ardalani2, Kathy L Frees3, Marzieh Mohseni2, Reza Mozafari2, Zohreh Mehrjoo2, Leila Jamali2, Saeideh Vaziri2, Tara Akhtarkhavari2, Niloofar Bazazzadegan2, Nooshin Nikzat2, Sanaz Arzhangi2, Farahnaz Sabbagh4, Hasan Otukesh5, Seyed Morteza Seifati6, Hossein Khodaei6, Maryam Taghdiri7, Nicole C Meyer3, Ahmad Daneshi8, Mohammad Farhadi8, Kimia Kahrizi2, Richard J H Smith9, Hela Azaiez3, Hossein Najmabadi2. 1. Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 2. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. 3. Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 4. Genetics Counseling Center, Kerman Welfare Institution, Kerman, Iran. 5. Division of Pediatric Nephrology, Hazrat-e-Ali Asghar Educational & Treatment Center, Iran University of Medical Sciences, Tehran, Iran. 6. Meybod Genetics Research Center, Shahid Fiazbakhsh Rehabilitation Comprehensive Center, Welfare Organization, Yazd, Iran. 7. Genetic Counseling Center, Shiraz Welfare Institution, Shiraz, Iran. 8. Head and Neck Surgery Department and Research Center, Iran University of Medical Sciences, Tehran, Iran. 9. Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, USA.
Abstract
BACKGROUND: Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. DESIGN: Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. RESULTS: 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. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. CONCLUSION: This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND: Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. DESIGN: Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. RESULTS: 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. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. CONCLUSION: This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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