Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.

Alvaro Gallego-Martinez,Teresa Requena,Jose A Lopez-Escamez,Pablo Roman-Naranjo

doi:10.3389/fgene.2019.00076

Abstract

Meniere's disease (MD) is a clinical spectrum of rare disorders characterized by vertigo attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to medium frequencies. Although it shows familial aggregation with incomplete phenotypic forms and variable expressivity, most cases are considered sporadic. The aim of this study was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD. We conducted a targeted-sequencing study including SNHL and familial MD genes in 890 MD patients to compare the frequency of rare variants in cases using three independent public datasets as controls. Patients with sporadic MD showed a significant enrichment of missense variants in SNHL genes that was not found in the controls. The list of genes includes GJB2, USH1G, SLC26A4, ESRRB, and CLDN14. A rare synonymous variant with unknown significance was found in the MARVELD2 gene in several unrelated patients with MD. There is a burden of rare variation in certain SNHL genes in sporadic MD. Furthermore, the interaction of common and rare variants in SNHL genes may have an additive effect on MD phenotype. This study will contribute to design a gene panel for the genetic diagnosis of MD.

Highlights

Meniere’s disease (MD, MIM 156000) is a chronic disorder of the inner ear characterized by episodes of vertigo, associated with low to middle frequency sensorineural hearing loss (SNHL), tinnitus and aural fullness (Lopez-Escamez et al, 2015)
We report that certain genes such as GJB2, USH1G, SLC26A4, and CLDN14 show an excess of missense variants in sporadic MD cases when compared to controls in the Iberian population, suggesting that several rare variants in these genes may contribute to the SNHL phenotype in sporadic MD
This study shows that patients with sporadic MD have an enrichment of few rare variants in certain hearing loss genes such as GJB2, SLC26A, or USH1G

Summary

Introduction

Meniere’s disease (MD, MIM 156000) is a chronic disorder of the inner ear characterized by episodes of vertigo, associated with low to middle frequency sensorineural hearing loss (SNHL), tinnitus and aural fullness (Lopez-Escamez et al, 2015). Heterogeneity in the phenotype is observed and some patients may have co-morbid conditions such as migraine or systemic autoimmune disorders (Gazquez et al, 2011; Caulley et al, 2017) This phenotypic spectrum can make the clinical diagnosis challenging considering that some of the symptoms overlap with other vestibular disorders such vestibular migraine (VM) or autoimmune inner ear disease (AIED) (Hietikko et al, 2011; Lempert et al, 2012; Mijovic et al, 2013; Requena et al, 2014b). More than 110 genes and ≈6,000 variants have been related to hereditary nonsyndromic hearing loss, making gene sequencing panels an essential tool for genetic diagnosis of hearing loss (The Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, 0000; Sloan-Heggen et al, 2016) Those genes include 45 genes associated to autosomal dominant SNHL and 71 genes related to recessive hearing loss (Shearer et al, 1999; Van Camp and Smith, 2018)

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