title: Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.
abstract: Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: A Eliot
authors.initials: AE
authors.lastname: Shearer
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Eppsteiner
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Booth
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Ephraim
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: José
authors.initials: J
authors.lastname: Gurrola
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: E Ann
authors.initials: EA
authors.lastname: Black-Ziegelbein
authors.affiliation: Agilent Technologies, Cedar Creek, TX 78612, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Agilent Technologies, Cedar Creek, TX 78612, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Ravi
authors.affiliation: Agilent Technologies, Cedar Creek, TX 78612, USA.
authors.forename: Angelica C
authors.initials: AC
authors.lastname: Giuffre
authors.affiliation: Agilent Technologies, Cedar Creek, TX 78612, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Happe
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Heidelberg, VIC 3084, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Hela
authors.initials: H
authors.lastname: Azaiez
authors.affiliation: Department of Otolaryngology, Faculty of Medicine, Medipol University, Istanbul 34083, Turkey.
authors.forename: Yildirim A
authors.initials: YA
authors.lastname: Bayazit
authors.affiliation: Department of Medical Biology and Genetics, University of Mersin, Mersin 33160, Turkey.
authors.forename: Mehmet Emin
authors.initials: ME
authors.lastname: Erdal
authors.affiliation: Otology and Neurotology Group CTS495, Center for Genomic and Oncological Research (GENyO), Granada 18012, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lopez-Escamez
authors.affiliation: Otology and Neurotology Group CTS495, Center for Genomic and Oncological Research (GENyO), Granada 18012, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gazquez
authors.affiliation: Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia.
authors.forename: Marta L
authors.initials: ML
authors.lastname: Tamayo
authors.affiliation: Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Gelvez
authors.affiliation: Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia.
authors.forename: Greizy Lopez
authors.initials: GL
authors.lastname: Leal
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY 11204, USA.
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.affiliation: Dor Yeshorim, The Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY 11211, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Ekstein
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, and the Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Otorhinolaryngology, School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Usami
authors.affiliation: Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran.
authors.forename: Niloofar
authors.initials: N
authors.lastname: Bazazzadegan
authors.affiliation: Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA; Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA; Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Braun
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA; Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Casavant
authors.affiliation: Agilent Technologies, Cedar Creek, TX 78612, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: LeProust
authors.affiliation: Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: richard-smith@uiowa.edu.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D016022:Case-Control Studies; D000072259:Connexin 26; D017630:Connexins; D005006:Ethnicity / Q000235:genetics*; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D010802:Phylogeny
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26