TMPRSS3 Gene Variants With Implications for Auditory Treatment and Counseling.

In Seok Moon,Heidi L Rehm,Varun Sagi,Andrew R Grant,Konstantina M Stankovic

doi:10.3389/fgene.2021.780874

Abstract

Objective: To identify and report novel variants in the TMPRSS3 gene and their clinical manifestations related to hearing loss as well as intervention outcomes. This information will be helpful for genetic counseling and treatment planning for these patients. Methods: Literature review of previously reported TMPRSS3 variants was conducted. Reported variants and associated clinical information was compiled. Additionally, cohort data from 18 patients, and their families, with a positive result for TMPRSS3-associated hearing loss were analyzed. Genetic testing included sequencing and copy number variation (CNV) analysis of TMPRSS3 and the Laboratory for Molecular Medicine’s OtoGenome-v1, -v2, or -v3 panels. Clinical data regarding patient hearing rehabilitation was interpreted along with their genetic testing results and in the context of previously reported cochlear implant outcomes in individuals with TMPRSS3 variants. Results: There have been 87 previously reported TMPRSS3 variants associated with non-syndromic hearing loss in more than 20 ancestral groups worldwide. Here we report occurrences of known variants as well as one novel variant: deletion of Exons 1–5 and 13 identified from our cohort of 18 patients. The hearing impairment in many of these families was consistent with that of previously reported patients with TMPRSS3 variants (i.e., typical down-sloping audiogram). Four patients from our cohort underwent cochlear implantation. Conclusion: Bi-allelic variants of TMPRSS3 are associated with down-sloping hearing loss regardless of ancestry. The outcome following cochlear implantation in patients with variants of TMPRSS3 is excellent. Therefore, cochlear implantation is strongly recommended for hearing rehabilitation in these patients.

Highlights

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of hereditary hearing loss
The TMPRSS3 gene encodes a type III transmembrane serine protease that is structurally defined by four functional domains: a transmembrane domain, low density lipoprotein receptor A domain, scavenger receptor cysteine rich domain, and a carboxyl terminal serine protease domain (Südhof et al, 1985; van Driel et al, 1987; Sarrias et al, 2004; Rawlings et al, 2010)
The TMPRSS3 gene is expressed in inner hair cells, spiral ganglion neurons (SGNs), the stria vascularis, and cochlear aqueducts of fetal cochlea (Guipponi et al, 2002)

Summary

Introduction

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of hereditary hearing loss. It accounts for about 70–80% of congenital hereditary hearing loss. The TMPRSS3 gene is expressed in inner hair cells, spiral ganglion neurons (SGNs), the stria vascularis, and cochlear aqueducts of fetal cochlea (Guipponi et al, 2002). The transmembrane serine protease 3 protein is thought to be involved in the development and maintenance of the inner ear, perilymph, endolymph and SGNs (Guipponi et al, 2002). While the function of the TMPRSS3 gene in the auditory system is not fully understood, its alteration has been linked with non-syndromic genetic hearing loss (DiStefano et al, 2018)

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Results

Conclusion