TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

Dominika Oziębło,Dariusz Plewczynski,Krzysztof Kochanek,Henryk Skarżyński,Michal Lazniewski,Grażyna Tacikowska,Anna Sarosiak,Marcin L Leja,Monika Ołdak

doi:10.1038/s41598-021-89645-y

Abstract

Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.

Highlights

Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner
Recessive variants detected in TBC1D24 may cause a spectrum of phenotypes, beginning with a mild form of familial infantile myoclonic epilepsy (FIME; OMIM #605021) and encompassing early-infantile epileptic encephalopathy 16 (EIEE16; OMIM #615338) and progressive myoclonic epilepsy ( PME4) that represent a combination of epilepsy with other variable features and ending with DOORS syndrome, a syndromic form of HL5
TBC1D24 variants causative for HL were identified in four probands (4/102), which corresponds to an approx. 4%-prevalence of TBC1D24related autosomal dominant HL (ADHL) in our cohort

Summary

Introduction

Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Increasing use of high throughput DNA sequencing methods has significantly improved the detection rate of genetic alterations causative of hearing loss (HL). It has resulted in discovering novel HL variants and genes and assigning new inheritance patterns to known HL g enes[1,2]. Another level of complexity is Scientific Reports | (2021) 11:10300. While the involvement of TBC1D24 in the development of a recessive form of HL is documented, with ten pathogenic variants identified so far[6,7,8,9,10], only two TBC1D24 pathogenic variants have been reported in the context of autosomal dominant HL (ADHL)[1,11,12]

Methods

Results

Conclusion