Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Abstract

Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

Fig. 1

The pipeline of bioinfomatic analysis

Fig. 2

The interaction graph of basic and diagnostic information for each sample. Positive diagnosis is influenced by ethnic, clinical, and phenotypic characteristics in sporadic hearing loss population. N for each combination of two reported characteristics for all combinations. Color/shading reflects the number of patients with the paired criteria, up to the maximum of n = 433

Fig. 3

Etiology classification and the representation analysis of the studied sporadic patient cohort. a Pathogenesis of 433 Chinese sporadic hearing loss patients. b The representation comparison of the studied 433 cases with 16,456 patients from our Clinic. Salmon pink indicated the positive diagnostic ratio of deafness panel (including 119 genes and mitochrodrial genome) in 433 cases. Light green indicated the positive diagnostic ratio of Sanger sequencing for common deafness genes (GJB2, SLC26A4, and mit12S rRNA) in 16,456 cases. The first three pairs of columns showed there are no significant differences of the positive testing ratio on GJB2, SLC26A4, mit12S rRNA between the two patient cohorts, which indicated that the cases enrolled in this study could represent a larger deafness population in China. The largest ethnic group in both cohorts was Han Chinese, comprising up to 95% of the total sample