title: DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss.
abstract: The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably, 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the α-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors. Although the majority are private mutations, four of them-p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys-were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of α-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.forename: Matías
authors.initials: M
authors.lastname: Morín
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Meyer
authors.forename: Fernando
authors.initials: F
authors.lastname: Mayo
authors.forename: Silvia
authors.initials: S
authors.lastname: Modamio-Hoybjor
authors.forename: Angeles
authors.initials: A
authors.lastname: Mencía
authors.forename: Leticia
authors.initials: L
authors.lastname: Olavarrieta
authors.forename: Carmelo
authors.initials: C
authors.lastname: Morales-Angulo
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Nishimura
authors.forename: Heather
authors.initials: H
authors.lastname: Workman
authors.forename: Adam P
authors.initials: AP
authors.lastname: DeLuca
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Taylor
authors.forename: Bruce
authors.initials: B
authors.lastname: Tompkins
authors.forename: Corey W
authors.initials: CW
authors.lastname: Goodman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.forename: Maarten Van
authors.initials: MV
authors.lastname: Wesemael
authors.forename: K
authors.initials: K
authors.lastname: Lachlan
authors.forename: A Eliot
authors.initials: AE
authors.lastname: Shearer
authors.forename: Terry A
authors.initials: TA
authors.lastname: Braun
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Casavant
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Moreno-Pelayo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001299:Audiometry / Q000379:methods; D002648:Child; D002675:Child, Preschool; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; C491350:TECTA protein, human