{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:06:49Z","timestamp":1777446409194,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T00:00:00Z","timestamp":1630713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008382","name":"Fundo Regional para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-007274"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007274"]}],"id":[{"id":"10.13039\/100008382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008382","name":"Fundo Regional para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000003 (DOCnet)"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000003 (DOCnet)"]}],"id":[{"id":"10.13039\/100008382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008382","name":"Fundo Regional para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-016390 (CancelStem)"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016390 (CancelStem)"]}],"id":[{"id":"10.13039\/100008382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BTM-TEC\/6706\/2020 (LEGOH)"],"award-info":[{"award-number":["PTDC\/BTM-TEC\/6706\/2020 (LEGOH)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BTM-TEC\/30164\/2017 (3DChroMe)"],"award-info":[{"award-number":["PTDC\/BTM-TEC\/30164\/2017 (3DChroMe)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C&gt;T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C&gt;T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers\u2019 RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C&gt;T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C&gt;T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445\u201310,900). Among 58 carriers (27 males (M)\u201331 females (F); 13\u201383 years), DGC occurred in 11 (18.9%; 4M\u20137F; average age 33 \u00b1 12) and LBC in 6 females (19.4%; average age 50 \u00b1 8). Herein, we demonstrated that the c.1901C&gt;T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.<\/jats:p>","DOI":"10.3390\/cancers13174464","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T10:59:12Z","timestamp":1630925952000},"page":"4464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The CDH1 c.1901C&gt;T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing"],"prefix":"10.3390","volume":"13","author":[{"given":"Rita","family":"Barbosa-Matos","sequence":"first","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences (BiotechHealth), ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0062-1865","authenticated-orcid":false,"given":"Rafaela","family":"Leal Silva","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"PhD Programme on Health Data Science, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Luzia","family":"Garrido","sequence":"additional","affiliation":[{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Ana Cerqueira","family":"Aguiar","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"Department of Clinical Pathology, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, 4520-211 Santa Maria da Feira, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-8908","authenticated-orcid":false,"given":"Jos\u00e9","family":"Garcia-Pelaez","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"Doctoral Programme on Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Ana","family":"Andr\u00e9","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7035-7422","authenticated-orcid":false,"given":"Susana","family":"Seixas","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"}]},{"given":"S\u00f3nia Passos","family":"Sousa","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"}]},{"given":"Lu\u00edsa","family":"Ferro","sequence":"additional","affiliation":[{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"L\u00facia","family":"Vilarinho","sequence":"additional","affiliation":[{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3377-0530","authenticated-orcid":false,"given":"Irene","family":"Gullo","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1032-4474","authenticated-orcid":false,"given":"Vitor","family":"Devezas","sequence":"additional","affiliation":[{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 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de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"CHUSJ, Centro Hospitar e Universit\u00e1rio de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8340-2264","authenticated-orcid":false,"given":"Carla","family":"Oliveira","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-804 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, 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