Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss

Abstract

TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 8 variants reported as causative for DFNA36. Here, we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss, with the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort being 0.17% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. Based on the audiometric data from the probands, family members and previously reported cases, we evaluated hearing deterioration for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.Asp543Asn. The results clearly indicated that the same haplotype was present despite the families being unrelated, supporting the contention that this variant occurred by founder mutation.

Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants

“…Only 1 of the 11 affected individuals in the present study had balance problems. This finding is in line with previous studies that found no vestibular symptoms associated with TMC1-associated HL cases [ 18 , 19 ].…”

“…All the affected individuals with recessively inherited TMC1 variants displayed severe-to-profound congenital hearing loss associated with down-sloping audiograms, where higher frequencies are the most severely affected. This is consistent with previous publications demonstrating that pathogenic recessive TMC1 variants cause moderate-to-profound hearing loss [ 17 , 18 , 19 , 20 ]. The individuals affected with ADSNHL displayed progressive postlingual sensorineural hearing loss that led to profound deafness and the need for CIs.…”

“…The individuals affected with ADSNHL displayed progressive postlingual sensorineural hearing loss that led to profound deafness and the need for CIs. In the previous publications, ADSNHL cases showed postlingual-onset progressive hearing loss, with predominant deterioration in the higher frequencies [ 18 , 19 , 20 , 21 ]. Only 1 of the 11 affected individuals in the present study had balance problems.…”

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

“…TMC1 gene mutations causing human deafness are divided into two categories: those referred to as DFNA36 (OMIM # 606705), which are autosomal dominant, and those termed DFNB7 (OMIM # 600974), which are autosomal recessive. Nonsense and frameshift mutations of TMC1 predicted to cause a loss of normal protein function through protein truncation are often detected in DFNB7/11 patients (Kraatari‐Tiri et al, 2022 ; Nishio & Usami, 2022 ). Our patient carried a break point in intron 8 of TMC1 , which interrupted the open reading frame.…”

CIB2 as a Ca2+Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity ofTMC1in Hearing Loss

“…The influx of Ca 2+ can modulate the activation and adaptation of the transducer current in a concentrationdependent manner 44,67 . However, the involvement of calcium in fast adaption of MET remains under debate [68][69][70] To date, over 100 pathogenic variants in TMC1 have been reported 71,72 , with only 8 of them responsible for DFNA36 (M113I, F313S, S320R, G417R, M418K, D543N, D572N and R759H).…”