Significant Mendelian genetic contribution to pediatric mild-to-moderate hearing loss and its comprehensive diagnostic approach

• Published in: Genetics in medicine Vol. 22; no. 6; pp. 1119 - 1128
• Main Authors: Kim, Bong Jik, Oh, Doo-Yi, Han, Jin Hee, Oh, Jayoung, Kim, Min Young, Park, Hye-Rim, Seok, Jungirl, Cho, Sung-dong, Lee, Sang-Yeon, Kim, Yoonjoong, Carandang, Marge, Kwon, In Sun, Lee, Seungmin, Jang, Jeong Hun, Choung, Yun-Hoon, Lee, Sejoon, Lee, Hakmin, Hwang, Sang Mee, Choi, Byung Yoon
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Elsevier Limited
• Subjects: Biomedical and Life Sciences; Biomedicine; Child; Etiology; Genetic Testing; Hearing loss; Hearing Loss - diagnosis; Hearing Loss - genetics; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Homozygote; Human Genetics; Humans; Infertility; Intercellular Signaling Peptides and Proteins; Laboratory Medicine; Pediatrics; copy-number variation (CNV); Mendelian genetic etiology; pediatric sensorineural hearing loss (SNHL); mild-to-moderate; STRC
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-020-0774-9

Purpose Timely diagnosis and identification of etiology of pediatric mild-to-moderate sensorineural hearing loss (SNHL) are both medically and socioeconomically important. However, the exact etiologic spectrum remains uncertain. We aimed to establish a genetic etiological spectrum, including copy-number variations (CNVs) and efficient genetic testing pipeline, of this defect. Methods A cohort of prospectively recruited pediatric patients with mild-to-moderate nonsyndromic SNHL from 2014 through 2018 ( n  = 110) was established. Exome sequencing, multiplex ligation-dependent probe amplification (MLPA), and nested customized polymerase chain reaction (PCR) for exclusion of a pseudogene, STRCP , from a subset ( n  = 83) of the cohort, were performed. Semen analysis was also performed to determine infertility ( n  = 2). Results Genetic etiology was confirmed in nearly two-thirds (52/83 = 62.7%) of subjects, with STRC -related deafness ( n  = 29, 34.9%) being the most prevalent, followed by MPZL2 -related deafness ( n  = 9, 10.8%). This strikingly high proportion of Mendelian genetic contribution was due particularly to the frequent detection of CNVs involving STRC in one-third (27/83) of our subjects. We also questioned the association of homozygous continuous gene deletion of STRC and CATSPER2 with deafness–infertility syndrome (MIM61102). Conclusion Approximately two-thirds of sporadic pediatric mild-to-moderate SNHL have a clear Mendelian genetic etiology, and one-third is associated with CNVs involving STRC . Based on this, we propose a new guideline for molecular diagnosis of these children.