{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T10:46:03Z","timestamp":1775731563827,"version":"3.50.1"},"reference-count":73,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ryan Foundation","award":["64311"],"award-info":[{"award-number":["64311"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30\u201360 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension and is characterized by tubulointerstitial damage, including tubular atrophy, interstitial inflammation, and fibrosis. Epidemiological studies showed familial clustering, suggesting an underlying genetic predisposition. This study aimed to identify genetic variants associated with CKDu in Sri Lankan populations using whole-exome sequencing (WES). Eighty-six individuals (47 CKDu patients and 39 controls) were recruited from endemic and non-endemic regions. Physiological, biochemical, and geographic parameters were recorded. DNA extracted from blood was subjected to WES to identify variants associated with CKDu. Results: A total of 171 unique variants across 121 genes were identified. Among the most prevalent genes were ATXN3, LFNG, PNLDC1, LINC02456, and HLA-DRB1. In the case\u2013control comparison, only LFNG showed statistically significant enrichment in affected individuals, whereas signals in ATXN3, PNLDC1, and LINC02456 were not statistically significant, but have an association with renal dysfunction, and thus are included as hypothesis-generating variant observations. HLA-DRB1 variants showed trends toward a protective haplotype. LFNG showed the greatest prevalence in affected individuals (71.7%), followed by PNLDC1 (63%), ATXN3 (56%), FIP1L1 (41%), and HLA-DRB1 (32%). Conclusion: Findings suggest genetic variants in combination with environmental factors may contribute to CKDu susceptibility in the Sri Lankan population. We underscore the multi-factorial nature of CKDu and highlight the need for integrative genomic and environmental research to elucidate disease mechanisms and inform targeted prevention strategies.<\/jats:p>","DOI":"10.3390\/ijms27083369","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T09:46:23Z","timestamp":1775727983000},"page":"3369","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Whole-Exome Sequencing-Based Exploration of Chronic Kidney Disease of Unknown Etiology (CKDu) in an Endemic Population in Sri Lanka"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5951-5311","authenticated-orcid":false,"given":"Wesley","family":"Tom","sequence":"first","affiliation":[{"name":"Molecular Diagnostic Research Laboratory, Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiran","family":"Weerakoon","sequence":"additional","affiliation":[{"name":"Center for Research, National Hospital-Kandy, University of Peradeniya, Kandy 20400, Sri Lanka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nirmalee","family":"Fernando","sequence":"additional","affiliation":[{"name":"Molecular Diagnostic Research Laboratory, Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isuru","family":"Hasantha","sequence":"additional","affiliation":[{"name":"Center for Research, National Hospital-Kandy, University of Peradeniya, Kandy 20400, Sri Lanka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj","family":"Bandara","sequence":"additional","affiliation":[{"name":"Center for Research, National Hospital-Kandy, University of Peradeniya, Kandy 20400, Sri Lanka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Krzyzanowski","sequence":"additional","affiliation":[{"name":"Molecular Diagnostic Research Laboratory, Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5479-9650","authenticated-orcid":false,"given":"Shanika","family":"Nanayakkara","sequence":"additional","affiliation":[{"name":"Sydney Dental School, Faculty of Medicine and Health, The University of Sydney, Sydney 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic","family":"Cosgrove","sequence":"additional","affiliation":[{"name":"Molecular Diagnostic Research Laboratory, Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3405-2912","authenticated-orcid":false,"given":"Nishantha","family":"Nanayakkara","sequence":"additional","affiliation":[{"name":"Center for Research, National Hospital-Kandy, University of Peradeniya, Kandy 20400, Sri Lanka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-3160","authenticated-orcid":false,"given":"M. Rohan","family":"Fernando","sequence":"additional","affiliation":[{"name":"Molecular Diagnostic Research Laboratory, Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.kisu.2021.11.003","article-title":"Epidemiology of chronic kidney disease: An update 2022","volume":"12","author":"Kovesdy","year":"2022","journal-title":"Kidney Int. Suppl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41581-024-00820-6","article-title":"Chronic kidney disease and the global public health agenda: An international consensus","volume":"20","author":"Francis","year":"2024","journal-title":"Nat. Rev. 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