title: Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.
abstract: OBJECTIVE
  Autosomal 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).
  
  
  METHODS
  After 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.Genet Med 18 4, 364-371.
authors.affiliation: 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.
authors.forename: Guney
authors.initials: G
authors.lastname: Bademci
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Foster
authors.affiliation: Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Nejat
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authors.lastname: Mahdieh
authors.affiliation: Faculty of Natural Sciences, Center of Excellence for Biodiversity, University of Tabriz, Tabriz, Iran.
authors.forename: Mortaza
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authors.lastname: Bonyadi
authors.affiliation: Division of Genetics, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Duygu
authors.identifier: http://orcid.org/0000-0001-7583-0349
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authors.lastname: Duman
authors.affiliation: Division of Genetics, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: F Basak
authors.initials: FB
authors.lastname: Cengiz
authors.affiliation: 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.
authors.forename: Ibis
authors.initials: I
authors.lastname: Menendez
authors.affiliation: 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.
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Horta
authors.affiliation: Kawsar's Human Genetic Research Center, Tehran, Iran.
authors.forename: Atefeh
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authors.lastname: Shirkavand
authors.affiliation: Kawsar's Human Genetic Research Center, Tehran, Iran.|Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Sirous
authors.initials: S
authors.lastname: Zeinali
authors.affiliation: Department of Medical Genetics, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey.
authors.forename: Asli
authors.initials: A
authors.lastname: Subasioglu
authors.affiliation: Department of Audiology, Hacettepe University Health Sciences Faculty, Ankara, Turkey.
authors.forename: Suna
authors.identifier: http://orcid.org/0000-0002-4656-099X
authors.initials: S
authors.lastname: Tokgoz-Yilmaz
authors.affiliation: Genetic Service, National Institute of Rehabilitation, Mexico D.F., Mexico.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Huesca-Hernandez
authors.affiliation: Genetic Service, National Institute of Rehabilitation, Mexico D.F., Mexico.
authors.forename: Maria
authors.initials: M
authors.lastname: de la Luz Arenas-Sordo
authors.affiliation: Genetic Service, National Institute of Rehabilitation, Mexico D.F., Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Dominguez-Aburto
authors.affiliation: Genetic Service, National Institute of Rehabilitation, Mexico D.F., Mexico.
authors.forename: Edgar
authors.initials: E
authors.lastname: Hernandez-Zamora
authors.affiliation: Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador.
authors.forename: Paola
authors.initials: P
authors.lastname: Montenegro
authors.affiliation: Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador.
authors.forename: Rosario
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador.
authors.forename: Germania
authors.initials: G
authors.lastname: Moreta
authors.affiliation: Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador.
authors.forename: Rodrigo
authors.identifier: http://orcid.org/0000-0001-5254-3072
authors.initials: R
authors.lastname: Vinueza
authors.affiliation: Molecular Genetic Lab, FFAA Hospital, Quito, Ecuador.
authors.forename: Franklin
authors.identifier: http://orcid.org/0000-0001-7188-5967
authors.initials: F
authors.lastname: Villegas
authors.affiliation: Audiology Department, Cuernavaca General Hospital, Morelos, Mexico.
authors.forename: Santiago
authors.initials: S
authors.lastname: Mendoza-Benitez
authors.affiliation: 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.
authors.forename: Shengru
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Otolaryngology, Faculty of Medicine, Yuzuncu Yıl University, Van, Turkey.
authors.forename: Nazim
authors.initials: N
authors.lastname: Bozan
authors.affiliation: Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara, Turkey.
authors.forename: Tulay
authors.initials: T
authors.lastname: Tos
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Eskisehir Osmangazi University, Eskisehir, Turkey.
authors.forename: Armagan
authors.initials: A
authors.lastname: Incesulu
authors.affiliation: Department of Audiology, Hacettepe University Health Sciences Faculty, Ankara, Turkey.
authors.forename: Gonca
authors.initials: G
authors.lastname: Sennaroglu
authors.affiliation: 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.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: Department of Radiology, Istanbul Zeynep Kamil Maternity and Children Training and Research Hospital, Istanbul, Turkey.
authors.forename: Hatice
authors.initials: H
authors.lastname: Ozturkmen-Akay
authors.affiliation: Department of Otorhinolaryngology, Dicle University School of Medicine, Diyarbakir, Turkey.
authors.forename: Muzeyyen
authors.initials: M
authors.lastname: Yildirim-Baylan
authors.affiliation: 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.
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mesh_terms: D000483:Alleles; D015331:Cohort Studies; D003638:Deafness / Q000175:diagnosis* / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D059472:Exome; D005808:Genes, Recessive; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation