Bong Jik Kim1,2, Doo-Yi Oh3, Jin Hee Han3, Jayoung Oh3, Min Young Kim3, Hye-Rim Park3, Jungirl Seok4,5, Sung-Dong Cho3, Sang-Yeon Lee3, Yoonjoong Kim3, Marge Carandang6, In Sun Kwon7, Seungmin Lee8, Jeong Hun Jang9, Yun-Hoon Choung9, Sejoon Lee10, Hakmin Lee11, Sang Mee Hwang12,13, Byung Yoon Choi14,15. 1. Department of Otolaryngology-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea. 2. Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Korea. 3. Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. 4. Department Otolaryngology-Head and Neck Surgery, National Cancer Center, Goyang, Korea. 5. Department of Biomedical Engineering, College of Medicine, Seoul National University, Seoul, Korea. 6. Department of Otorhinolaryngology-Head and Neck Surgery, East Avenue Medical Center, Metro Manila, Philippines. 7. Chungnam National University Hospital Clinical Trials Center, Daejeon, Korea. 8. R&D Center, ENCell Co.Ltd, Seoul, Korea. 9. Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea. 10. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea. 11. Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea. 12. Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea. 13. Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. 14. Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. choiby2010@gmail.com. 15. Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea. choiby2010@gmail.com.
Abstract
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.
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.