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

• Type of Material: Article
• Authors: Yongyi Yuan, Chinese Peoples Liberation Army General Hospital; Qi Li, Emory University; Yu Su, Chinese Peoples Liberation Army General Hospital; Qiongen Lin, China National GeneBank; Xue Gao, PLA Rocket Force Characteristic Medical Center; Hankui Liu, China National GeneBank; Shasha Huang, Chinese Peoples Liberation Army General Hospital; Dongyang Kang, Chinese Peoples Liberation Army General Hospital; Norman Wendell Todd Jr., Emory University; Douglas Mattox, Emory University; Jiannguo Zhang, China National GeneBank; Xi Lin, Emory University; Pu Dai, Chinese Peoples Liberation Army General Hospital
• Language: English
• Date: 2020-02-01
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41431-019-0510-6
• Title of Journal or Parent Work: EUROPEAN JOURNAL OF HUMAN GENETICS
• Volume: 28
• Issue: 2
• Start Page: 231
• End Page: 243
• Grant/Funding Information: This study was supported by grants from National Key Research and Development Project of China (2016YFC1000706) and National Natural Science Foundation of China (81873704) and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund (2017-JQPY-001) to YY, National Natural Science Foundation of China (81570929) to XG, National Key Research and Development Project (2016YFC1000700, 2016YFC1000704) and National Natural Science Foundation of China (81730029) and Natural Science Foundation Key Project of Beijing (7191011) to PD, National Institute on Deafness and other Communication Disorders (RO1 DC006483 and RO1 DC014496) to XL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.
• Keywords: DIAGNOSTICS; Genetics & Heredity; DEAFNESS GENES; CAPTURE; Biochemistry & Molecular Biology; PENDRED-SYNDROME; ENLARGED VESTIBULAR AQUEDUCT; CLINICAL-EVALUATION; Life Sciences & Biomedicine; HEREDITARY HEARING-LOSS; MUTATIONS; IMPAIRMENT; ALLELE FREQUENCY; Science & Technology
• Research Categories: Chemistry, Biochemistry; Biology, Genetics

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.