{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:47:47Z","timestamp":1777391267977,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SNUH Kun-hee Lee Child Cancer &amp; Rare Disease Project","award":["FP-2022-00001-004"],"award-info":[{"award-number":["FP-2022-00001-004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The ClC-K channels CLCNKA and CLCNKB are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter\u2019s syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in CLCNKA in trans with a contiguous deletion of CLCNKA and CLCNKB. Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the CLCNKA_CLCNKB contiguous deletion. The proband that harbors the CLCNKA_CLCNKB variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of CLCNKA_CLCNKB suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the CLCNKA_CLCNKB intergenic region, especially in undiagnosed SNHL patients with a single hit in CLCNKA.<\/jats:p>","DOI":"10.3390\/ijms242317077","type":"journal-article","created":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T04:59:16Z","timestamp":1701579556000},"page":"17077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Expanding Genotype\u2013Phenotype Correlation of CLCNKA and CLCNKB Variants Linked to Hearing Loss"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0719-9599","authenticated-orcid":false,"given":"Yejin","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"GENOME INSIGHT TECHNOLOGY Inc., Daejeon 34051, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heeyoung","family":"Seok","sequence":"additional","affiliation":[{"name":"Department of Transdisciplinary Research and Collaboration, Genomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-5853","authenticated-orcid":false,"given":"Seongyeol","family":"Park","sequence":"additional","affiliation":[{"name":"GENOME INSIGHT TECHNOLOGY Inc., Daejeon 34051, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang-Yeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"},{"name":"Department of Genomic Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea"},{"name":"Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fphys.2010.00155","article-title":"Physiology and pathophysiology of ClC-K\/barttin channels","volume":"1","author":"Fahlke","year":"2010","journal-title":"Front. 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