{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:17:09Z","timestamp":1791404229840,"version":"4.3.3"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006483","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (<jats:italic>CFTR<\/jats:italic>) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of <jats:italic>CFTR<\/jats:italic> variants across ancestries is critical for revolutionizing molecular diagnoses of CF.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of <jats:italic>CFTR<\/jats:italic> variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American\/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific <jats:italic>CFTR<\/jats:italic> variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant <jats:italic>CFTR<\/jats:italic> genotypes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We detected over 4000 <jats:italic>CFTR<\/jats:italic> variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique <jats:italic>CFTR<\/jats:italic> variants [<jats:italic>n<\/jats:italic>\u2009=\u20092212], while the American group had the least unique variants [<jats:italic>n<\/jats:italic>\u2009=\u200923]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G\u2009&gt;\u2009A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05].<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We leveraged the UKBB database to comprehensively characterize the broad spectrum of <jats:italic>CFTR<\/jats:italic> variants across ancestries. The detection of over 4000 <jats:italic>CFTR<\/jats:italic> variants, including several ancestry-specific and uncharacterized <jats:italic>CFTR<\/jats:italic> variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13073-024-01316-5","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T11:02:30Z","timestamp":1711018950000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences"],"prefix":"10.1186","volume":"16","author":[{"given":"Justin E.","family":"Ideozu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget M.","family":"Riley-Gillis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sri R.","family":"Paladugu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedik","family":"Rahimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethi","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Dorr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hara","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashvani","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey F.","family":"Waring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Vasanthakumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"1316_CR1","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.jcf.2021.10.011","volume":"21","author":"KS Raraigh","year":"2022","unstructured":"Raraigh KS, et al. 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