Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

RESEARCH ARTICLE Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans Bong Jik Kim1☯, Ah Reum Kim1☯, Chung Lee2,3, So Young Kim1, Nayoung K. D. Kim2, Mun Young Chang1, Jihye Rhee1, Mi-Hyun Park4, Soo Kyung Koo4, Min Young Kim5, Jin Hee Han5, Seung-ha Oh1, Woong-Yang Park2,6, Byung Yoon Choi5* a11111 1 Department of Otorhinolaryngology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea, 2 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea, 3 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, Korea, 4 Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do, Korea, 5 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea, 6 Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Korea ☯ These authors contributed equally to this work. * OPEN ACCESS Citation: Kim BJ, Kim AR, Lee C, Kim SY, Kim NKD, Chang MY, et al. (2016) Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans. PLoS ONE 11(10): e0165680. doi:10.1371/journal. pone.0165680 Editor: David Meyre, McMaster University, CANADA Received: August 14, 2016 Accepted: October 14, 2016 Published: October 28, 2016 Copyright: © 2016 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Also, we have submitted the novel variants of CDH23 that we detected by next generation sequencing to the Leiden Open Variation Database (LOVD) (http://databases.lovd.nl/shared/genes/ CDH23) (submission numbers 0000081436 and 0000081437). Funding: This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (www.mohw.go.kr/) (HI14C1867 and HI15C1632 Abstract CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NSSNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF. PLOS ONE | DOI:10.1371/journal.pone.0165680 October 28, 2016 1 / 13 CDH23 and Progressive Postlingual Deafness in Koreans to BYC); and also by the Korea National Institute of Health intramural research grant 4861-307-210-13 (2012-NG61004-00 to SKK); and Korea Biobank Project (http://www.nih.go.kr/NIH_NEW/main.jsp) (4851-307, KBP-2014-035 to SKK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Introduction Mutations of CDH23 (NM_022124) have been associated with type 1D Usher Syndrome (USH1D) and nonsyndromic hearing loss (DFNB12), in a recessively transmitted manner [1, 2]. USH1D is associated with severe manifestations, including congenital profound deafness vestibular areflexia, and visual problems due to retinitis pigmentosa. Conversely, DFNB12, is characterized by prelingual-onset nonsyndromic sensorineural hearing loss (SNHL) without the impairment of vestibular or visual functions [3]. The importance of CDH23 as a deafness gene has increasingly been recognized [4, 5]. In a Japanese study, CDH23 mutations were reported to be frequent after GJB2 and SLC26A4 in children and adults with hearing impairment [6]. Recently, CDH23 mutations have been reported in the Korean deaf population [7, 8], and genetic loads of CDH23 and its implications in the Korean pediatric population have also recently been reported [9]. Accordingly, p.P240L in CDH23 proved to exert a strong founder effect in the Korean pediatric population with severe-to-profound nonsyndromic SNHL. Although CDH23 has been well established as a deafness gene, it is challenging to delineate its function by a functional assay due to its relatively large size with 69 exons and encoded cadherin 23, which includes a protein of 3,354 amino acids with 27 extracellular cadherin (EC) domains, a single transmembrane domain, and a short cytoplasmic domain [4, 5, 10]. CDH23 related hearing loss is known to be associated with its role in the tip links of the inner ear hair cells. Tip links are extracellular filaments that is proposed to act as a gate for the mechanotransduction channel. In other words, it transduces the mechanical forces that arise from the sound waves and head movement, allowing one to hear and maintain balance [11]. The interaction between protocadherin-15 (PCDH15) and CDH23—both localized in the upper and lower parts of the tip link complex—has been reported to form tip links [12]. Accordingly, both CDH23 and PCDH15 are necessary for normal mechanotransduction, and mutations in these genes have been associated with sensory impairment [10, 13]. CDH23 related hearing loss in USH1D and DFNB12 has mostly been associated with either congenital or prelingual-onset hearing loss [5]. However, some CDH23 mutations have been reported to be associated with postlingual-onset moderate hearing loss in humans [6, 14]. Further (...truncated)