title: Whole Exome Sequencing Reveals Homozygous Mutations in RAI1, OTOF, and SLC26A4 Genes Associated with Nonsyndromic Hearing Loss in Altaian Families (South Siberia).
abstract: Hearing loss (HL) is one of the most common sensorineural disorders and several dozen genes contribute to its pathogenesis. Establishing a genetic diagnosis of HL is of great importance for clinical evaluation of deaf patients and for estimating recurrence risks for their families. Efforts to identify genes responsible for HL have been challenged by high genetic heterogeneity and different ethnic-specific prevalence of inherited deafness. Here we present the utility of whole exome sequencing (WES) for identifying candidate causal variants for previously unexplained nonsyndromic HL of seven patients from four unrelated Altaian families (the Altai Republic, South Siberia). The WES analysis revealed homozygous missense mutations in three genes associated with HL. Mutation c.2168A>G (SLC26A4) was found in one family, a novel mutation c.1111G>C (OTOF) was revealed in another family, and mutation c.5254G>A (RAI1) was found in two families. Sanger sequencing was applied for screening of identified variants in an ethnically diverse cohort of other patients with HL (n = 116) and in Altaian controls (n = 120). Identified variants were found only in patients of Altaian ethnicity (n = 93). Several lines of evidences support the association of homozygosity for discovered variants c.5254G>A (RAI1), c.1111C>G (OTOF), and c.2168A>G (SLC26A4) with HL in Altaian patients. Local prevalence of identified variants implies possible founder effect in significant number of HL cases in indigenous population of the Altai region. Notably, this is the first reported instance of patients with RAI1 missense mutation whose HL is not accompanied by specific traits typical for Smith-Magenis syndrome. Presumed association of RAI1 gene variant c.5254G>A with isolated HL needs to be proved by further experimental studies.
authors.affiliation: Arizona Research Laboratories, Division of Biotechnology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Сhurbanov
authors.affiliation: Arizona Research Laboratories, Division of Biotechnology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Karafet
authors.affiliation: SB RAS Genomics Core Facility, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.|Novosibirsk State University, Novosibirsk, Russian Federation.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Morozov
authors.affiliation: Novosibirsk State University, Novosibirsk, Russian Federation.|Laboratory of Human Molecular Genetics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.
authors.forename: Valeriia Yu
authors.initials: VY
authors.lastname: Mikhalskaia
authors.affiliation: Novosibirsk State University, Novosibirsk, Russian Federation.|Laboratory of Human Molecular Genetics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Zytsar
authors.affiliation: SB RAS Genomics Core Facility, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Bondar
authors.affiliation: Novosibirsk State University, Novosibirsk, Russian Federation.|Laboratory of Human Molecular Genetics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation.
authors.forename: Olga L
authors.identifier: http://orcid.org/0000-0003-1352-3591
authors.initials: OL
authors.lastname: Posukh
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics*; D059472:Exome; D005091:Exons; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D005843:Geography; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D012800:Siberia; D000076988:Sulfate Transporters; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C118457:OTOF protein, human; C431552:RAI1 protein, human; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D015534:Trans-Activators; D014157:Transcription Factors