The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients

Abstract

Background/Objectives:MYO3A belongs to the unconventional myosin superfamily, and the myosin IIIa protein localizes on the tip of the stereocilia of vestibular and cochlear hair cells. Deficiencies in MYO3A have been reported to cause the deformation of hair cells into abnormally long stereocilia with an increase in spacing. MYO3A is a rare causative gene of autosomal recessive sensorineural hearing loss (DFNB30), with only 13 cases reported to date. In this study, we aimed to elucidate the phenotypes caused by MYO3A variations. Methods: Massively parallel DNA sequencing was performed on 15,684 Japanese hearing loss patients (mean age 27.5 ± 23.1 years old, 6574 male, 8612 female and 498 patients for whom information was unavailable), identifying nine candidate patients with MYO3A variants. Results: We identified eight causative MYO3A variants by massively parallel DNA sequencing, including six novel variants, and reported nine individuals possessing MYO3A gene variants, which is the largest group of non-related patients yet to be detected. Our findings confirmed that MYO3A variants cause progressive hearing loss, with its onset varying from birth to the second decade, eventually leading to severe-to-profound hearing loss. Conclusions: We clarified that patients with MYO3A gene variants present with late-onset, progressive hearing loss. Our findings have enabled us to predict the outcomes of hearing loss in patients with candidate MYO3A gene variants and to provide intervention in a timely manner.

Keywords: DFNB30; MYO3A; late-onset hearing loss; non-syndromic hearing loss; progressive hearing loss.

Figure 1

Pedigree and audiograms for the families of each MYO3A-associated HL patient identified in this study. The variants identified in this study are indicated in the figure. Pedigrees have been enumerated #1 to #9 for clarification. Solid line: hearing threshold in the right ear; Dashed line: hearing threshold in the left ear.

Figure 2

(A) Overlapping audiograms from all MYO3A-associated HL patients identified in this study. (B) Detailed progression analysis of hearing deterioration for patients with MYO3A-associated HL. Each dot indicates the pure-tone average (PTA; average of hearing thresholds for 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz) and age of each patient. Dotted line indicates the linear regression.

Figure 3

All reported pathogenic MYO3A variants and their locations in the MYO3A gene. Novel variants identified in this study are indicated in red, variants identified in this study and previous reports are indicated in orange and variants reported to have an AD inheritance pattern are indicated in blue. *: stop codon.