{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:01:18Z","timestamp":1784174478646,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-40-50-GMM"],"award-info":[{"award-number":["AS-40-50-GMM"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-GC-110-MD02"],"award-info":[{"award-number":["AS-GC-110-MD02"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Clinical presentation is heterogeneous for autosomal dominant nonsyndromic hearing loss (ADNSHL). Variants of KCNQ4 gene is a common genetic factor of ADNSHL. Few studies have investigated the association between hearing impairment and the variant c.546C&gt;G of KCNQ4. Here, we investigated the phenotype and clinical manifestations of the KCNQ4 variant. Study subjects were selected from the participants of the Taiwan Precision Medicine Initiative. In total, we enrolled 12 individuals with KCNQ4 c.546C&gt;G carriers and 107 non-carriers, and performed pure tone audiometry (PTA) test and phenome-wide association (PheWAS) analysis for the patients. We found that c.546C&gt;G variant was related to an increased risk of hearing loss. All patients with c.546C&gt;G variant were aged &gt;65 years and had sensorineural and high frequency hearing loss. Of these patients, a third (66.7%) showed moderate and progressive hearing loss, 41.7% complained of tinnitus and 16.7% complained of vertigo. Additionally, we found a significant association between KCNQ4 c.546C&gt;G variant, aortic aneurysm, fracture of lower limb and polyneuropathy in diabetes. KCNQ4 c.546C&gt;G is likely a potentially pathogenic variant of ADNSHL in the elderly population. Genetic counseling, annual audiogram and early assistive listening device intervention are highly recommended to prevent profound hearing impairment in this patient group.<\/jats:p>","DOI":"10.3390\/genes12111711","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"1711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A KCNQ4 c.546C&gt;G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-9434","authenticated-orcid":false,"given":"Ting-Ting","family":"Yen","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-5304","authenticated-orcid":false,"given":"I-Chieh","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Men-Wei","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yi","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Hsiang","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Heng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Department of Health Care Management, National Taipei University of Nursing and Health Sciences, Taipei 108306, Taiwan"},{"name":"Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung 40704, Taiwan"},{"name":"Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Hung","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-3065","authenticated-orcid":false,"given":"Yi-Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Rong Hsing Research Center for Translational Medicine & Ph.D. Program in Translational Medicine, Taichung 402202, Taiwan"},{"name":"College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-6029","authenticated-orcid":false,"given":"Rong-San","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"},{"name":"Rong Hsing Research Center for Translational Medicine & Ph.D. Program in Translational Medicine, Taichung 402202, Taiwan"},{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/eurpub\/ckr176","article-title":"Global and regional hearing impairment prevalence: An analysis of 42 studies in 29 countries","volume":"23","author":"Stevens","year":"2013","journal-title":"Eur. J. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening\u2014A silent revolution","volume":"354","author":"Morton","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1542\/peds.2005-3168","article-title":"Slight\/mild sensorineural hearing loss in children","volume":"118","author":"Wake","year":"2006","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1097\/AUD.0000000000000345","article-title":"Prevalence of Hearing Loss among a Representative Sample of Canadian Children and Adolescents, 3 to 19 Years of Age","volume":"38","author":"Feder","year":"2017","journal-title":"Ear Heart"},{"key":"ref_5","unstructured":"Homepage, H.H.L. (2021, October 21). Welcome to the Hereditary Hearing Loss Homepage. Available online: https:\/\/hereditaryhearingloss.org\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S0140-6736(05)71047-3","article-title":"Sensorineural hearing loss in children","volume":"365","author":"Smith","year":"2005","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.ijporl.2004.12.002","article-title":"Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing","volume":"69","author":"Finsterer","year":"2005","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.mrrev.2008.08.002","article-title":"Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?","volume":"681","author":"Hilgert","year":"2009","journal-title":"Mutat. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00439-016-1648-8","article-title":"Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss","volume":"135","author":"Bierer","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_10","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (1993). GeneReviews(\u00ae), University of Washington."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8940","DOI":"10.1523\/JNEUROSCI.2085-07.2007","article-title":"Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear","volume":"27","author":"Holt","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.1073\/pnas.97.8.4333","article-title":"KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway","volume":"97","author":"Kharkovets","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.neuroscience.2019.05.012","article-title":"Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a DFNA2-Like Mouse Model","volume":"410","author":"Carignano","year":"2019","journal-title":"Neuroscience"},{"key":"ref_14","unstructured":"Cooper, D.N., Stenson, P.D., Phillips, A.D., Evans, K., Heywood, S., Hayden, M.J., Chapman, M.M., Mort, M.E., Azevedo, L., and Millar, D.S. (2021, October 21). The Human Gene Mutation Database. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/gene.php?gene=KCNQ4."},{"key":"ref_15","unstructured":"ClinVar (2021, October 21). KCNQ4 and Pathogenic, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?term=KCNQ4+and+pathogenic."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.gene.2019.04.064","article-title":"Bi-allelic Pro291Leu variant in KCNQ4 leads to early onset non-syndromic hearing loss","volume":"705","author":"Ramzan","year":"2019","journal-title":"Gene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1074\/jbc.M110.179010","article-title":"Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2","volume":"286","author":"Kim","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1159\/000096154","article-title":"Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan","volume":"12","author":"Su","year":"2007","journal-title":"Audiol. Neurootol."},{"key":"ref_19","first-page":"1","article-title":"Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment","volume":"51","author":"Jung","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.bbrc.2006.07.053","article-title":"Studies of the effect of ionomycin on the KCNQ4 channel expressed in Xenopus oocytes","volume":"348","author":"Su","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41525-021-00178-9","article-title":"Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese","volume":"6","author":"Wei","year":"2021","journal-title":"NPJ Genom. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0092-8674(00)80556-5","article-title":"KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness","volume":"96","author":"Kubisch","year":"1999","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/hmg\/8.7.1321","article-title":"Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families","volume":"8","author":"Coucke","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00424-020-02496-w","article-title":"Age-related hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway","volume":"473","author":"Vona","year":"2021","journal-title":"Pflugers Arch."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.etap.2018.08.009","article-title":"Genetic variation in KCNQ4 gene is associated with susceptibility to noise-induced hearing loss in a Chinese population","volume":"63","author":"Guo","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/HYPERTENSIONAHA.111.187427","article-title":"Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired beta-adrenoceptor-mediated relaxation of renal arteries in hypertension","volume":"59","author":"Chadha","year":"2012","journal-title":"Hypertension"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, X., Xu, Y., An, M., and Zeng, Q. (2019). The risk factors for diabetic peripheral neuropathy: A meta-analysis. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212574"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jvs.2010.05.090","article-title":"Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals","volume":"52","author":"Kent","year":"2010","journal-title":"J. Vasc. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1001\/archinte.160.10.1425","article-title":"The aneurysm detection and management study screening program: Validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators","volume":"160","author":"Lederle","year":"2000","journal-title":"Arch. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1161\/01.ATV.16.8.963","article-title":"Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study","volume":"16","author":"Alcorn","year":"1996","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1001\/archotol.1997.01900060015002","article-title":"Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2","volume":"123","author":"Marres","year":"1997","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1177\/000348940211100312","article-title":"Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2\/KCNQ4 family","volume":"111","author":"Huygen","year":"2002","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1001\/archinternmed.2011.728","article-title":"Hearing loss and falls among older adults in the United States","volume":"172","author":"Lin","year":"2012","journal-title":"Arch. Intern. Med."},{"key":"ref_36","first-page":"159","article-title":"Single-nucleotide polymorphism genotyping for disease association studies","volume":"108","author":"Fornage","year":"2005","journal-title":"Methods Mol. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:35Z","timestamp":1760167295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/11\/1711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,27]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["genes12111711"],"URL":"https:\/\/doi.org\/10.3390\/genes12111711","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,27]]}}}