{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:40:46Z","timestamp":1791247246402,"version":"4.1.0"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"\n Background<\/jats:title>\n \n Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder characterized by the development of numerous colorectal polyps and a high predisposition to colorectal cancer, primarily caused by germline variants in the\n APC<\/jats:italic>\n gene. This study aimed to identify and functionally validate a novel\n APC<\/jats:italic>\n variant in a Chinese FAP pedigree.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A three-generation Chinese FAP pedigree was recruited. Peripheral blood samples were collected from family members to extract genomic DNA. Whole-exome sequencing (WES) was performed to screen candidate variants, and Sanger sequencing was used for verification. SW480 cells (endogenously deficient in functional APC) were divided into three groups: empty vector group, APC-wild-type (APC-WT) group, and APC-mutant group. Western blot analysis was conducted to detect \u03b2-catenin protein expression levels, to evaluate the functional impact of the identified variant.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The proband\u2019s FAP-associated colorectal cancer was identified as exhibiting microsatellite instability high (MSI-H) with a classic MLH1\/PMS2 dual loss pattern. A novel germline variant\n APC<\/jats:italic>\n c.3799dup was identified in all affected family members but was absent in unaffected individuals. Western blot analysis showed that \u03b2-catenin protein levels in the APC-WT group were significantly lower than those in the APC-Mutant group (P &lt; 0.05) and the empty vector group (P &lt; 0.01). This indicated that the c.3799 dup variant abolished APC\u2019s ability to promote \u03b2-catenin degradation, leading to sustained activation of the Wnt\/\u03b2-catenin pathway.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The novel\n APC<\/jats:italic>\n variant c.3799 dup is a pathogenic variant associated with FAP. Our findings expand the spectrum of known\n APC<\/jats:italic>\n variants and provide functional evidence for the pathogenicity of this variant. The rare co-occurrence of FAP and MSI-H in the proband enriches the molecular phenotypic spectrum of FAP-related tumors.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fgene.2026.1776361","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T22:10:13Z","timestamp":1773612613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel pathogenic APC variant identified in a Chinese pedigree with familial adenomatous polyposis"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenyu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiyu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Oncology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengli","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Hunan Province Clinical Research Center for Genetic Birth Defects and Rare Diseases, The Second Xiangya Hospital, Central South University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1159\/000015360","article-title":"Familial adenomatous polyposis (FAP) and its gene, APC","volume":"86","author":"Bodmer","year":"1999","journal-title":"Cytogenet Cell. 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