{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T07:45:54Z","timestamp":1782114354248,"version":"3.54.5"},"reference-count":13,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T00:00:00Z","timestamp":1664323200000},"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":"<jats:p>Pathogenic and likely pathogenic (P\/LP) germline variants in the tumor suppressor gene <jats:italic>CDH1<\/jats:italic> (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. <jats:italic>CDH1<\/jats:italic> variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P\/LP <jats:italic>CDH1<\/jats:italic> variants. Patients with P\/LP <jats:italic>CDH1<\/jats:italic> variants who were enrolled in a prospective clinical trial were reviewed (NCT03030404). The cohort included 299 individuals from 153 families that had 80 unique P\/LP variants in <jats:italic>CDH1<\/jats:italic>. The rate of CLP was 19% (29\/153) in families reporting CLP in at least one family member, and 2.7% (8\/299) among individuals with confirmed germline <jats:italic>CDH1<\/jats:italic> P\/LP variants. There were 22 unique variants in <jats:italic>CDH1<\/jats:italic> among the 29 families that reported CLP, or a CLP rate of 27.5% per variant (22\/80). 10 of the variants were not previously reported to be associated with CLP. We observed that 24% (7\/29) of CLP-associated gene variants involved large-scale (\u22651 exon) deletions. Among families with CLP, 69% (20\/29) had a member diagnosed with gastric cancer, and 79% (23\/29) had a member with breast cancer, which were similar to rates observed in non-CLP families (<jats:italic>p<\/jats:italic> &amp;gt;0.3 for both). Our analysis suggests that the prevalence of CLP in families with germline <jats:italic>CDH1<\/jats:italic> P\/LP variants was high in this large cohort, and there was no genotype-phenotype pattern. Genetic testing for <jats:italic>CDH1<\/jats:italic> variants should be considered in families with CLP and history of either diffuse-type gastric or lobular breast cancer.<\/jats:p>","DOI":"10.3389\/fgene.2022.1012025","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T06:33:06Z","timestamp":1664346786000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Frequent cleft lip and palate in families with pathogenic germline CDH1 variants"],"prefix":"10.3389","volume":"13","author":[{"given":"Benjamin L.","family":"Green","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace-Ann","family":"Fasaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah G.","family":"Samaranayake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Duemler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A.","family":"Gamble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy L.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e386","DOI":"10.1016\/S1470-2045(20)30219-9","article-title":"Hereditary diffuse gastric cancer: Updated clinical practice guidelines","volume":"21","author":"Blair","year":"2020","journal-title":"Lancet. Oncol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.ajhg.2018.04.009","article-title":"Mutations in the epithelial cadherin-p120-catenin complex cause mendelian non-syndromic cleft lip with or without cleft palate","volume":"102","author":"Cox","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: Understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1136\/jmg.2005.031385","article-title":"Cleft lip\/palate and CDH1\/E-cadherin mutations in families with hereditary diffuse gastric cancer","volume":"43","author":"Frebourg","year":"2006","journal-title":"J. Med. 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Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4255","DOI":"10.1038\/onc.2008.62","article-title":"The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers","volume":"27","author":"Karam","year":"2008","journal-title":"Oncogene"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1001\/jama.297.21.2360","article-title":"Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer","volume":"297","author":"Kaurah","year":"2007","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","first-page":"4769","DOI":"10.1038\/s41388-018-0304-2","article-title":"E-cadherin in contact inhibition and cancer","volume":"37","author":"Mendonsa","year":"2018","journal-title":"Oncogene"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1001\/jamaoncol.2019.1208","article-title":"Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers","volume":"5","author":"Roberts","year":"2019","journal-title":"JAMA Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"E391","DOI":"10.3390\/genes11040391","article-title":"CDH1 mutation distribution and type suggests genetic differences between the etiology of orofacial clefting and gastric cancer","volume":"11","author":"Selvanathan","year":"2020","journal-title":"Genes"},{"key":"B11","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrm3802","article-title":"Dynamic contacts: Rearranging adherens junctions to drive epithelial remodelling","volume":"15","author":"Takeichi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"S51","DOI":"10.4103\/0970-0358.57187","article-title":"Syndromes and anomalies associated with cleft","volume":"42","author":"Venkatesh","year":"2009","journal-title":"Indian J. Plast. Surg."},{"key":"B13","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1136\/jmedgenet-2019-105991","article-title":"Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria","volume":"56","author":"Xicola","year":"2019","journal-title":"J. Med. Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1012025\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T06:33:07Z","timestamp":1664346787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1012025\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,28]]},"references-count":13,"alternative-id":["10.3389\/fgene.2022.1012025"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1012025","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,28]]},"article-number":"1012025"}}