Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort |
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| Affiliation: | 1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA;2. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran;3. Faculty of Natural Sciences, Center of Excellence forBiodiversity, University of Tabriz, Tabriz, Iran;4. Division of Genetics, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey;5. Kawsar’s Human Genetic Research Center, Tehran, Iran;6. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran;7. Department of Medical Genetics, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey;8. Department of Audiology, Hacettepe University Health Sciences Faculty, Ankara, Turkey;9. Genetic Service, National Institute of Rehabilitation, Mexico D.F., Mexico;10. Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador;11. Audiology Department, Cuernavaca General Hospital, Morelos, Mexico;12. Department of Otolaryngology, Faculty of Medicine, Yuzuncu Yıl University, Van, Turkey;13. Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey;14. Department of Otolaryngology, Head and Neck Surgery, Eskisehir Osmangazi University, Eskisehir, Turkey;15. Department of Radiology, Istanbul Zeynep Kamil Maternity and Children Training and Research Hospital, Istanbul, Turkey;16. Department of Otorhinolaryngology, Dicle University School of Medicine, Diyarbakir, Turkey |
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| Abstract: | PurposeAutosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families. |
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