{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T19:11:25Z","timestamp":1785179485499,"version":"3.55.0"},"reference-count":78,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G &gt; A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.<\/jats:p>","DOI":"10.3390\/genes13030400","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T09:34:38Z","timestamp":1645608878000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-7169","authenticated-orcid":false,"given":"Jihenne","family":"Ben Aissa-Haj","sequence":"first","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kabbage","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1159-6482","authenticated-orcid":false,"given":"Houcemeddine","family":"Othmen","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0438-6310","authenticated-orcid":false,"given":"Patrick","family":"Saulnier","sequence":"additional","affiliation":[{"name":"Genomic Platform Molecular Biopathology Unit, URA3655 Inserm, US23 CNRS, Gustave Roussy, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifa Tounsi","family":"Kettiti","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Jaballah-Gabteni","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azer","family":"Ferah","sequence":"additional","affiliation":[{"name":"Laboratory of Venoms and Therapeutic 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Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Samir","family":"Boubaker","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Mousaddak","family":"Azzouz","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"},{"name":"Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Department of Biology and Pathology-Cancer Genetics Laboratory-Gustave Roussy, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.5114\/pg.2018.80001","article-title":"Epidemiology of gastric cancer: Global trends, risk factors and prevention","volume":"14","author":"Rawla","year":"2019","journal-title":"Gastroenterol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1016\/S0140-6736(16)30354-3","article-title":"Gastric cancer","volume":"388","author":"Sagaert","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1158\/1055-9965.EPI-13-1057","article-title":"Gastric Cancer: Descriptive Epidemiology, Risk Factors, Screening, and Prevention","volume":"23","author":"Karimi","year":"2014","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0895-4356(02)00534-6","article-title":"Gastric cancer epidemiology and risk factors","volume":"56","author":"Kelley","year":"2003","journal-title":"J. Clin. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3875","DOI":"10.3748\/wjg.v20.i14.3875","article-title":"Gastric cancer in Africa: Current management and outcomes","volume":"20","author":"Asombang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3748\/wjg.v12.i3.354","article-title":"Epidemiology of gastric cancer","volume":"12","author":"Crew","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/apm.1965.64.1.31","article-title":"The Two Histological Main Types of Gastric Carcinoma: Diffuse and so-Called in-Testinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification","volume":"64","author":"Lauren","year":"1965","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1002\/1097-0142(19930515)71:10<2926::AID-CNCR2820711007>3.0.CO;2-X","article-title":"Epidemiology of intestinal and diffuse types of gastric carcinoma a time-trend study in finland with comparison between studies from high-and low-risk areas","volume":"71","author":"Nevalainen","year":"1993","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.3892\/ol.2016.4337","article-title":"Lauren classification and individualized chemotherapy in gastric cancer","volume":"11","author":"Ma","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/32918","article-title":"E-cadherin germline mutations in familial gastric cancer","volume":"392","author":"Guilford","year":"1998","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1016\/S1470-2045(14)71016-2","article-title":"Familial gastric cancer: Genetic susceptibility, pathology, and implications for management","volume":"16","author":"Oliveira","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1093\/jnci\/92.21.1781","article-title":"Report on the First Meeting of the International Collaborative Group on Hereditary Gastric Cancer","volume":"92","author":"Park","year":"2000","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1136\/jmedgenet-2015-103094","article-title":"Hereditary diffuse gastric cancer: Updated clinical guidelines with an emphasis on germline CDH1 mutation carriers","volume":"52","author":"Vogelaar","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1001\/jamaoncol.2014.168","article-title":"Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond","volume":"1","author":"Hansford","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10120-011-0116-3","article-title":"A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer","volume":"15","author":"Seevaratnam","year":"2011","journal-title":"Gastric Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1039\/b719215k","article-title":"Cadherins in development and cancer","volume":"4","author":"Stemmler","year":"2008","journal-title":"Mol. Biosyst."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3756","DOI":"10.1007\/s00018-008-8281-1","article-title":"The cell-cell adhesion molecule E-cadherin","volume":"65","author":"Berx","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/path.4152","article-title":"An \u03b1-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer","volume":"229","author":"Majewski","year":"2013","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/ijc.21460","article-title":"Response of ovarian carcinomas to gefitinib-carboplatin-paclitaxel combination is not associated with EGFR kinase domain somatic mutations","volume":"118","author":"Lacroix","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1186\/s12864-016-3289-7","article-title":"Comparative genomics of European avian pathogenic E. Coli (APEC)","volume":"17","author":"Cordoni","year":"2016","journal-title":"BMC Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/humu.22981","article-title":"HGVS Recommendations for the Description of Sequence Variants: 2016 Update","volume":"37","author":"Dalgleish","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1002\/humu.23650","article-title":"Specifications of the ACMG\/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants","volume":"39","author":"Lee","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7913","DOI":"10.1093\/nar\/gky372","article-title":"Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico\/in vitro studies: An international collaborative effort","volume":"46","author":"Leman","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative Protein Modelling by Satisfaction of Spatial Restraints","volume":"234","author":"Blundell","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1002\/prot.22716","article-title":"Sub-angstrom modeling of complexes between flexible peptides and globular proteins","volume":"78","author":"Raveh","year":"2010","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"pl2","DOI":"10.1126\/stke.2192004pl2","article-title":"Computational Alanine Scanning of Protein-Protein Interfaces","volume":"2004","author":"Kortemme","year":"2004","journal-title":"Sci. STKE"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1016\/j.bpj.2015.08.015","article-title":"MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories","volume":"109","author":"McGibbon","year":"2015","journal-title":"Biophys. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1093\/nar\/gnf056","article-title":"Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification","volume":"30","author":"Schouten","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cell.2010.01.017","article-title":"Dynamic and Static Interactions between p120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion","volume":"141","author":"Ishiyama","year":"2010","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1093\/jnci\/djz229","article-title":"CDH1 on Multigene Panel Testing: Look Before You Leap","volume":"112","author":"Katona","year":"2019","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/mgg3.197","article-title":"Panel testing reveals nonsense and missense CDH 1 mutations in families without hereditary diffuse gastric cancer","volume":"4","author":"Huynh","year":"2016","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.16.00021","article-title":"Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges","volume":"1","author":"Lowstuter","year":"2017","journal-title":"JCO Precis. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1136\/jmedgenet-2015-103153","article-title":"Hereditary diffuse gastric cancer syn-drome: Improved performances of the 2015 testing criteria for the identification of probands with a CDH1 germline mutation","volume":"52","author":"Benusiglio","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1053\/j.gastro.2015.06.003","article-title":"Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients with a Germline Mutation in CDH1","volume":"149","author":"Vogelaar","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4083","DOI":"10.1038\/s41467-018-06581-8","article-title":"Germline pathogenic variants of 11 breast cancer genes in 7051 Japanese patients and 11,241 controls","volume":"9","author":"Momozawa","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/j.str.2004.09.014","article-title":"Complementarity of Structure Ensembles in Protein-Protein Binding","volume":"12","author":"Leckner","year":"2004","journal-title":"Structure"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Paul, F., and Weikl, T.R. (2016). How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates. PLoS Comput. Biol., 12.","DOI":"10.1371\/journal.pcbi.1005067"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nrc2521","article-title":"Derailed endocytosis: An emerging feature of cancer","volume":"8","author":"Mosesson","year":"2008","journal-title":"Nat. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/ncb758","article-title":"Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex","volume":"4","author":"Fujita","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1093\/emboj\/21.8.1948","article-title":"A presenilin-1\/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions","volume":"21","author":"Marambaud","year":"2002","journal-title":"EMBO J."},{"key":"ref_43","first-page":"73","article-title":"E-Cadherin\/\u03b2-Catenin Complex and the Epithelial Barrier","volume":"2011","author":"Tian","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1093\/hmg\/ddp046","article-title":"Germline CDH1 deletions in hereditary diffuse gastric cancer families","volume":"18","author":"Oliveira","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","first-page":"297","article-title":"Epithelial E- and P-cadherins: Role and clinical significance in cancer","volume":"1826","author":"Paredes","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/s41598-018-19491-y","article-title":"A Novel Modeling in Mathematical Biology for Classification of Signal Peptides","volume":"8","author":"Ehsan","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/nature02342","article-title":"Structure of the signal recognition particle interacting with the elongation-arrested ribosome","volume":"427","author":"Halic","year":"2004","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nature08870","article-title":"Recognition of a signal peptide by the signal recognition particle","volume":"465","author":"Janda","year":"2010","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s12943-018-0859-0","article-title":"E-cadherin signal sequence disruption: A novel mechanism underlying hereditary cancer","volume":"17","author":"Figueiredo","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s41416-021-01673-7","article-title":"CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer","volume":"126","author":"Adib","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1136\/jmedgenet-2018-105807","article-title":"Clinical spectrum and pleiotropic nature of CDH1 germline mutations","volume":"56","author":"Figueiredo","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/hmg\/dds497","article-title":"Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts","volume":"22","author":"Vogelaar","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1002\/cncr.25876","article-title":"Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer","volume":"117","author":"Xie","year":"2011","journal-title":"Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","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":"ref_55","doi-asserted-by":"crossref","unstructured":"Boujemaa, M., Hamdi, Y., Mejri, N., Romdhane, L., Ghedira, K., Bouaziz, H., Benna, H.E., Labidi, S., Dallali, H., and Jaidane, O. (2021). Germline copy number variations in BRCA1\/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0245362"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12967-018-1504-9","article-title":"Family specific genetic predisposition to breast cancer: Results from Tunisian whole exome sequenced breast cancer cases","volume":"16","author":"Hamdi","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s12967-019-1961-9","article-title":"Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: Investigation of a Tunisian Lynch syndrome family with discordant twins","volume":"17","author":"Tounsi","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.3389\/fgene.2020.552971","article-title":"Identification of Novel BRCA1 and RAD50 Mutations Associated with Breast Cancer Predisposition in Tunisian Patients","volume":"11","author":"Mighri","year":"2020","journal-title":"Front. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Mezzi, N., Messaoud, O., Mkaouar, R., Zitouna, N., Romdhane, S., Abdessalem, G., Charfeddine, C., Maazoul, F., Ouerteni, I., and Hamdi, Y. (2021). Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved. Genes, 12.","DOI":"10.3390\/genes12111820"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1136\/jmg.38.1.49","article-title":"E-cadherinis not frequently mutated in hereditary gastric cancer","volume":"38","author":"Avizienyte","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1136\/jmg.2006.043133","article-title":"CDH1\/E-cadherin germline mutations in early-onset gastric cancer","volume":"43","author":"Bacani","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Mucaki, E.J., Caminsky, N.G., Perri, A.M., Lu, R., Laederach, A., Halvorsen, M., Knoll, J.H.M., and Rogan, P.K. (2016). A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genomics., 9.","DOI":"10.1186\/s12920-016-0178-5"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1590\/1678-4685-gmb-2014-0342","article-title":"CDH1 mutations in gastric cancer patients from northern Brazil identified by Next- Generation Sequencing (NGS)","volume":"39","author":"Amador","year":"2016","journal-title":"Genet. Mol. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1007\/s10120-019-00945-9","article-title":"Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil","volume":"22","author":"Guindalini","year":"2019","journal-title":"Gastric Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Norero, E., Alarcon, M.A., Hakkaart, C., de Mayo, T., Mellado, C., Garrido, M., Aguayo, G., Lagos, M., Torres, J., and Calvo, A. (2019). Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20204980"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.1093\/hmg\/ddn249","article-title":"Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer","volume":"17","author":"Figueiredo","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1136\/jmg.2004.018275","article-title":"Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria","volume":"41","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ajhg.2012.05.021","article-title":"Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes","volume":"91","author":"Johnston","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1007\/s00109-006-0091-z","article-title":"A model to infer the pathogenic significance of CDH1 germline missense variants","volume":"84","author":"Suriano","year":"2006","journal-title":"J. Mol. Med. Berl. Ger."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Bustos-Carpinteyro, A.R., Oliveira, C., Sousa, A., Oliveira, P., Pinheiro, H., Carvalho, J., Maga\u00f1a-Torres, M.T., Flores-Miramontes, M.G., Aguilar-Lemarroy, A., and Jave-Su\u00e1rez, L.F. (2019). CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5294-0"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/humu.10068","article-title":"Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred","volume":"19","author":"Oliveira","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Jalkh, N., Chouery, E., Haidar, Z., Khater, C., Atallah, D., Ali, H., Al-Mulla, M.R., Al-Mulla, F., and Megarbane, A. (2017). Next-generation sequencing in familial breast cancer patients from Lebanon. BMC Med. Genomics., 10.","DOI":"10.1186\/s12920-017-0244-7"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.1136\/jmg.2003.015594","article-title":"Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients","volume":"41","author":"Keller","year":"2004","journal-title":"J. Med Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/bcr295","article-title":"Low frequency of E-cadherin alterations in familial breast cancer","volume":"3","author":"Salahshor","year":"2001","journal-title":"Breast Cancer Res. BCR."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/humu.10067","article-title":"Novel germlineCDH1mutations in hereditary diffuse gastric cancer families","volume":"19","author":"Humar","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_76","first-page":"493","article-title":"New Variants in the CDH1 Gene in Iranian Families with Hereditary Diffuse Gastric Cancer","volume":"11","author":"Kheirollahi","year":"2020","journal-title":"Middle East J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s12029-018-0082-7","article-title":"Novel Variants and Copy Number Variation in CDH1 Gene in Iranian Patients with Sporadic Diffuse Gastric Cancer","volume":"50","author":"Moridnia","year":"2018","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/path.2426","article-title":"Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer","volume":"216","author":"Barber","year":"2008","journal-title":"J. Pathol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:25:21Z","timestamp":1760135121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,23]]},"references-count":78,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["genes13030400"],"URL":"https:\/\/doi.org\/10.3390\/genes13030400","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-617841\/v1","asserted-by":"object"}]},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,23]]}}}