Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss

Nobuko Yamamoto,Kaoru Ogawa,Noriko Morita,Tatsuo Matsunaga,Sawako Masuda,Yasuyuki Nishi,Kazunori Namba,Atsuko Nakano,Shin Masuda,Masato Fujioka,Hideki Mutai,Kimitaka Kaga

doi:10.1186/s13023-017-0708-z

Abstract

BackgroundTo date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL.MethodsSubjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling.ResultsPathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have the family histories compatible with sporadic or autosomal recessive.ConclusionsTECTA mutations were identified in 6.0% of MFSNHL. These mutations were more frequent in patients with shallow U-shaped audiograms than those with U-shaped audiograms, and in families which have the family histories compatible with autosomal dominant than those with the family histories compatible with sporadic or autosomal recessive.

Highlights

To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features
There were 21 patients with U-shaped audiograms meeting the GENDEAF criterion in one or both ears (1.7% of patients who received U-shaped audiogram selection) and 46 with shallow U-shaped audiograms (3.9% of patients who were excluded by U-shaped audiogram selection)
Histories of these 67 patients with U-shaped or shallow U-shaped audiograms were compatible with autosomal dominant (AD) in 23 patients (34.3%), autosomal recessive (AR) in 10 patients (14.9%), and sporadic in 34 patients (50.7%)

Summary

Introduction

102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. There are four genes reported to cause mid-frequency hearing loss: EYA4 (DFNA10), TECTA (DFNA8/12, DFNB21), COL11A2 (DFNA13), and CCDC50 (DFNA44) [3] Among these four genes, mutations in TECTA are most frequently reported [4,5,6,7], and autosomal dominant (AD) TECTA mutations (DFNA8/12) account for 2.9–4% of all autosomal dominant non-syndromic sensorineural hearing loss (ADNSHL) [4, 7]. The α-tectorin protein is composed of three distinct modules (Fig. 1) [9]: an entactin-G1-like domain (ENT); a zonadhesin-like (ZA) domain, comprising one von Willebrand factor type C repeat, four von Willebrand factor type D repeats, and three trypsin inhibitor-like repeats; and a zona pellucida (ZP) domain Both AD and autosomal recessive (AR) inheritance patterns have been reported for mutations in TECTA (DFNA8/12, OMIM # 601543; DFNB21, OMIM # 603629 [8, 10]). Mouse models of deafness due to TECTA mutations exhibit deformation of the tectorial membrane [11,12,13]; the detailed mechanism by which these mutations cause mid-frequency hearing loss remains unknown

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