{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T03:54:52Z","timestamp":1778558092049,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"St. Antonius Onderzoeksfonds","award":["842002001"],"award-info":[{"award-number":["842002001"]}]},{"name":"St. Antonius Onderzoeksfonds","award":["10070012010004"],"award-info":[{"award-number":["10070012010004"]}]},{"name":"ZonMW TopZorg St. Antonius Care","award":["842002001"],"award-info":[{"award-number":["842002001"]}]},{"name":"ZonMW TopZorg St. Antonius Care","award":["10070012010004"],"award-info":[{"award-number":["10070012010004"]}]},{"name":"ZonMW Topspecialistische Zorg en Onderzoek","award":["842002001"],"award-info":[{"award-number":["842002001"]}]},{"name":"ZonMW Topspecialistische Zorg en Onderzoek","award":["10070012010004"],"award-info":[{"award-number":["10070012010004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: TOM1L2 c.421T &gt; C p.(Y141H) and TDP1c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality.<\/jats:p>","DOI":"10.3390\/ijms24032790","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T02:21:12Z","timestamp":1675304472000},"page":"2790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis"],"prefix":"10.3390","volume":"24","author":[{"given":"Karlijn","family":"Groen","sequence":"first","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-8416","authenticated-orcid":false,"given":"Joanne J.","family":"van der Vis","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Department of Clinical Chemistry, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aernoud A.","family":"van Batenburg","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin M.","family":"Kazemier","sequence":"additional","affiliation":[{"name":"Center of Translational Immunology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Division of Hearts and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Hearts and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coline H. M.","family":"van Moorsel","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17074","DOI":"10.1038\/nrdp.2017.74","article-title":"Idiopathic Pulmonary Fibrosis","volume":"3","author":"Martinez","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","first-page":"1","article-title":"Genetic Disorders of the Surfactant System: Focus on Adult Disease","volume":"30","author":"Grutters","year":"2021","journal-title":"Eur. Respir. 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