Novel Mutations and Mutation Combinations of TMPRSS3 Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment.

Xue Gao,Guo-Jian Wang,Yu Su,Yong-Yi Yuan,Pu Dai,Xi Lin,Jin-Cao Xu

doi:10.1155/2017/4707315

Abstract

Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

Highlights

Hearing impairment is the most common sensory disorder
Our results indicate that Autosomal recessive nonsyndromic hearing impairment (ARNSHI) patients with TMPRSS3 mutations are good candidates for residual hearing preservation by cochlear implantation, which is in accordance with the evaluation of cochlear implantation outcomes reported by Chung et al [8]
This study showed that the combination of p.(Phe13Serfs∗12) and p.Ala306Thr results in prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, and II: 5)

Summary

Introduction

Hearing impairment is the most common sensory disorder. Identifying the genetic basis of deafness provides important information for the diagnosis, intervention, and treatment of this condition. Nonsyndromic hearing impairment, is extremely genetic heterogeneous. More than 200 genetic loci have been mapped, and 100 deafness genes have been identified (http://hereditaryhearingloss.org/). Autosomal recessive nonsyndromic hearing impairment (ARNSHI) is the most common type and accounts for ∼80% of cases of inherited hearing loss. A large majority of recessive mutations are associated with congenital, nonprogressive, and severeto-profound hearing loss [1]. Exceptions were observed in the TMPRSS3 gene, which was reported to be associated with two different phenotypes: DFNB10-associated hearing impairment has been reported to be prelingual (OMIM 605511), whereas DFNB8-associated hearing impairment is typically late onset and postlingual (OMIM 601072). The compound heterozygosity for a mild and severe mutations leads to postlingual hearing loss, whereas the combination of two severe mutations leads to profound hearing impairment with a prelingual onset [2]. The TMPRSS3 gene has been identified as the gene responsible for ARNSHI in several populations, including Asian, Mediterranean, and Caucasian populations [2,3,4,5]

Methods

Results

Discussion

Conclusion