{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:10:58Z","timestamp":1771330258893,"version":"3.50.1"},"reference-count":61,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND &amp; AIMS<\/jats:title><jats:p>Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole\u2010exome sequencing (WES) has contributed to understanding the molecular basis of very early\u2010onset IBD, but rare protein\u2010altering genetic variants have not been identified for early\u2010onset PSC. We performed WES in patients diagnosed with PSC\u00a0\u2264\u00a012\u00a0years to investigate the contribution of rare genetic variants to early\u2010onset PSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>In this multicentre study, WES was performed on 87 DNA samples from 29 patient\u2010parent trios with early\u2010onset PSC. We selected rare (minor allele frequency\u00a0&lt;\u00a02%) coding and splice\u2010site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in\u2010house developed algorithm (GAVIN), and PSC\u2010relevant variants were selected using gene expression data and gene function.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The 36 candidate genes for early\u2010onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14831","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T21:10:54Z","timestamp":1613682654000},"page":"1044-1057","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Exome sequencing in patient\u2010parent trios suggests new candidate genes for early\u2010onset primary sclerosing cholangitis"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-7776","authenticated-orcid":false,"given":"Sjoukje\u2010Marije","family":"Haisma","sequence":"first","affiliation":[{"name":"Department of Paediatric Gastroenterology Hepatology and Nutrition University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rinse K.","family":"Weersma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology University of Groningen University Medical Center Groningen Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7420-7125","authenticated-orcid":false,"given":"Maria E.","family":"Joosse","sequence":"additional","affiliation":[{"name":"Department of Paediatric Gastroenterology Erasmus University Medical Center Sophia Children's Hospital Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara A. 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