Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families

Pengcheng Xu,Hu Peng,Tao Yang,Jun Xu

doi:10.1155/2020/8872185

Abstract

Genetic hearing loss is a common sensory disorder, and its cause is highly heterogeneous. In this study, by targeted next-generation sequencing of 414 known deafness genes, we identified compound heterozygous mutations p.R34X/p.M413T in TMC1 and p.S3417del/p.R1407T in MYO15A in two recessive Chinese Han deaf families. Intrafamilial cosegregation of the mutations with the hearing phenotype was confirmed in both families by the Sanger sequencing. Auditory features of the affected individuals are consistent with that previously reported for recessive mutations in TMC1 and MYO15A. The two novel mutations identified in this study, p.M413T in TMC1 and p.R1407T in MYO15A, are classified as likely pathogenic according to the guidelines of ACMG. Our study expanded the mutation spectrums of TMC1 and MYO15A and illustrated that genotype-phenotype correlation in combination with next-generation sequencing may improve the accuracy for genetic diagnosis of deafness.

Highlights

Congenital hearing impairment is a common birth defect worldwide, occurring in approximately 1-2 per 1000 infants
More than 100 genes have been reported to be associated with nonsyndromic hearing loss (NSHL), including 76 autosomal recessive nonsyndromic hearing loss (ARNSHL) genes, 48 autosomal dominant nonsyndromic hearing loss (ADNSHL) genes, and 5 X-linked nonsyndromic hearing loss genes (Hereditary Hearing Loss Homepage; https://hereditaryhearingloss.org/, updated in January 2020)
We presented the clinical characterization and genetic analysis of two Chinese Han families affected by ARNSHL

Summary

Introduction

Congenital hearing impairment is a common birth defect worldwide, occurring in approximately 1-2 per 1000 infants. The TMC1 gene is located on chromosome 9q21 and contains 24 exons that encodes a 760 amino acid membrane protein TMC1 with six transmembrane domains [12, 13]. TMC1 is a pore-forming subunit of the mechanotransduction complex that is predicted to have transmembrane domains with intracellular N and C termini and one conserved TMC domain [14]. It has been reported that mutations in TMC1 may cause both prelingual profound autosomal recessive deafness DFNB7/11 and postlingual progressive autosomal dominant deafness DFNA36 [13]. More than 60 mutations in TMC1 are reported worldwide [15], with the recessive mutations predominantly associated with prelingual severe-to-profound hearing loss [15, 16]

Methods

Results

Conclusion