{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T02:11:35Z","timestamp":1770516695006,"version":"3.49.0"},"reference-count":21,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,3,2]],"date-time":"2019-03-02T00:00:00Z","timestamp":1551484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Germline mutations affecting the exonuclease domains of <jats:italic>POLE<\/jats:italic> and <jats:italic>POLD1<\/jats:italic> predispose to colorectal adenomas and carcinoma. Here, we aimed to screen the exonuclease domains to find the genetic causes of multiple colorectal polyps in unexplained cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a custom next\u2010generation sequencing panel, we sequenced the exonuclease domains of <jats:italic>POLE<\/jats:italic> and <jats:italic>POLD1<\/jats:italic> in 332 index patients diagnosed with multiple colorectal polyps without germline alteration in colorectal polyposis predisposing genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified two variants of unknown significance. One germline <jats:italic>POLD1<\/jats:italic> c.961G&gt;A, p.(Gly321Ser) variant was found in two cases. The first patient was diagnosed with multiple polyps at age 35 and colorectal cancer (CRC) at age 37, with no known family history of CRC. The second patient was diagnosed with CRC at age 44 and cumulatively developed multiple polyps; this patient had two sisters with endometrial cancer who did not carry the variant. Furthermore, we identified a novel <jats:italic>POLD1<\/jats:italic> c.955\u00a0T&gt;G, p.(Cys319Gly) variant in a patient diagnosed with multiple colorectal adenomas at age 40. Co\u2010segregation analysis showed that one sister who cumulatively developed multiple adenomas from age 34, and another sister who developed CRC at age 38 did not carry the variant. We did not identify pathogenic variants in <jats:italic>POLE<\/jats:italic> and <jats:italic>POLD1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study confirms the low frequency of causal variants in these genes in the predisposition for multiple colorectal polyps, and also establishes that these genes are a rare cause of the disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.603","type":"journal-article","created":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T05:09:49Z","timestamp":1551589789000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Low frequency of <i>POLD1<\/i> and <i>POLE<\/i> exonuclease domain variants in patients with multiple colorectal polyps"],"prefix":"10.1002","volume":"7","author":[{"given":"Fadwa A.","family":"Elsayed","sequence":"first","affiliation":[{"name":"Department of Pathology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carli M. J.","family":"Tops","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5351-1870","authenticated-orcid":false,"given":"Maartje","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dina","family":"Ruano","sequence":"additional","affiliation":[{"name":"Department of Pathology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2682-2603","authenticated-orcid":false,"given":"Hans F. A.","family":"Vasen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Morreau","sequence":"additional","affiliation":[{"name":"Department of Pathology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3025-0882","authenticated-orcid":false,"given":"Frederik","family":"J. Hes","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-7730","authenticated-orcid":false,"given":"Tom","family":"van Wezel","sequence":"additional","affiliation":[{"name":"Department of Pathology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,3,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng828"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.75"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.048"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.5689"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2016.00036"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.242"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15810"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.10.052"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.252"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.01.054"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1651562"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200007133430201"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra012242"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/371075a0"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2503"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.7.735"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22314"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29396"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu058"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-006-9103-y"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3287"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmgg3.603","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.603","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.603","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.603","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T08:22:22Z","timestamp":1694334142000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.603"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,2]]},"references-count":21,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1002\/mgg3.603"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.603","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,2]]},"assertion":[{"value":"2018-09-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00603"}}