Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease

A Soto-Varela,P Roman-Naranjo,M.D.C Moleon,A Escalera-Balsera,D Bächinger,J.A Lopez-Escamez,M Gomez-Fiñana,I Aran,A.H Eckhard

doi:10.1016/j.heares.2021.108329

Abstract

The MYO7A gene encodes a motor protein with a key role in the organization of stereocilia in auditory and vestibular hair cells. Rare variants in the MYO7A (myosin VIIA) gene may cause autosomal dominant (AD) or autosomal recessive (AR) sensorineural hearing loss (SNHL) accompanied by vestibular dysfunction or retinitis pigmentosa (Usher syndrome type 1B). Familial Meniere's disease (MD) is a rare inner ear syndrome mainly characterized by low-frequency sensorineural hearing loss and episodic vertigo associated with tinnitus. Familial aggregation has been found in 6–8% of sporadic cases, and most of the reported genes were involved in single families. Thus, this study aimed to search for relevant genes not previously linked to familial MD. Through exome sequencing and segregation analysis in 62 MD families, we have found a total of 1 novel and 8 rare heterozygous variants in the MYO7A gene in 9 non-related families. Carriers of rare variants in MYO7A showed autosomal dominant or autosomal recessive SNHL in familial MD. Additionally, some novel and rare variants in other genes involved in the organization of the stereocilia links such as CDH23, PCDH15 or ADGRV1 co-segregated in the same patients. Our findings reveal a co-segregation of rare variants in the MYO7A gene and other structural myosin VIIA binding proteins involved in the tip and ankle links of the hair cell stereocilia. We suggest that recessive digenic inheritance involving these genes could affect the ultrastructure of the stereocilia links in familial MD.

Highlights

Monogenic sensorineural hearing loss (SNHL) is sometimes associated with vestibular dysfunction, leading to a complex clinical syndrome which may range from episodic vertigo to a progressive vestibular dysfunction (Roman-Naranjo et al, 2017)
We found two Loss of Function (LoF) variants: a start loss variant p.Met1Ile found in F1 segregating the Meniere’s disease (MD) in the three affected individuals of this family (Supplemental Table 2), and a novel stop gain variant p.Trp1545Ter found in F6
The p.Arg873Trp variant in the MYO7A gene found in F5 has been previously observed in two patients with Usher Syndrome type 2 (Västinsalo et al, 2013); and the MYO7A variant found in F2 (p.Arg336His) has been already observed in patients with Usher Syndrome type 1, being classified as a disease causing variant (Jaijo et al, 2006)

Summary

Introduction

Monogenic sensorineural hearing loss (SNHL) is sometimes associated with vestibular dysfunction, leading to a complex clinical syndrome which may range from episodic vertigo to a progressive vestibular dysfunction (Roman-Naranjo et al, 2017). Mutations in the MYO7A gene are involved in several types of SNHL with variable vestibular dysfunction, including autosomal recessive (DFNB2), autosomal dominant (DFNA11) SNHL, and Usher syndrome type 1B (USH1B) (Friedman et al, 2020). 4 of these individuals presented vestibular symptoms (Weil et al, 1997) Later, this family was revaluated, reporting mild retinal degeneration in 5 patients and an abnormal vestibular function in 7 patients. DFNA11 has been reported in different families with progressive mild-to-profound hearing loss and an age of onset ranging from 1 to 47 years. USH1B disease is an autosomal recessive disorder characterized by profound deafness affecting all frequencies, variable vestibular dysfunction, and early onset retinitis pigmentosa (RP) (Friedman et al, 2020)

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