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.

Figure 1

a Scheme depicting the different domains of the α-tectorin protein. The novel pathogenic mutations and those previously identified are shown at the top and at the bottom, respectively. The mutations described in this study among the previously identified are highlighted in bold. b Highly conserved amino acids of the α-tectorin protein based on Conseq scores, showing conserved protein domains (to scale). c Domains and regions of the α-tectorin protein. The amino acids and exons that comprise each domain are indicated. ENT, entactin domain; V0 (vWFC), von Willebrand factor C domain; V1 (vWFD1), von Willebrand factor D domain 1; V2 (vWFD2), von Willebrand factor D domain 2; V3 (vWFD3), von Willebrand factor D domain 3; V4 (vWFD4), von Willebrand factor D domain 4; ZP, zonapellucia domain; ZA, zonadhesin region; TIL1, trypsin inhibitor like cysteine rich domain 1; TIL2, trypsin inhibitor like cysteine rich domain 2; TIL3, trypsin inhibitor like cysteine rich domain 3.

Figure 2

a - b Pedigrees of the Spanish families S324 and S726. Black and white symbols indicate the affected and the unaffected subjects, respectively. Haplotypes are represented by bars, with haplotype associated with hearing loss in black. The numbers placed beside chromosomes are the allelic sizes for each microsatellite marker. The box shows the relative order and genetic distances of the microsatellite markers spanning the DFNA8/12 region. On the right are audiograms showing the hearing threshold values obtained from five different patients of each family - III:1, III:8, II:2, II:6 and I:1 of S324 and III:4, III:2, II:7, II:4 and II:3 of S726. Each graph point represents the average hearing loss for the right and left ears. c Transient evoked otoacoustic emissions (TEOAEs) of patients III:5, III:4 and III:2 of family S726.

Figure 3

Pedigree of the Spanish family S1385. The marks and symbols are as described in Fig. 2. The relative order of the TECTA gene and the microsatellite markers within the DFNA8/12 genetic interval is indicated. The mutation found in the family is notated as TECTA:p.Thr1866Met. Audiograms show the mean of the hearing threshold values obtained from the left and right ears in the patients II:5, II,4, II:2, I:1, I:2 and III:3 at the time of recording.