{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298628,"version":"4.5.0"},"reference-count":20,"publisher":"BMJ","issue":"9","funder":[{"name":"Hunter Medical Research Institute Cancer Detection and Therapy Research Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/0020x6414","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015676","name":"NSW Health Pathology","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100015676","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinical and Health Service Research Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,5,11]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Epithelial cell adhesion molecule (\n                    <jats:italic>EPCAM<\/jats:italic>\n                    )-associated Lynch syndrome arises from deletions at the 3\u2032-end of\n                    <jats:italic>EPCAM<\/jats:italic>\n                    that disrupt transcriptional termination, generate read-through transcripts and cause epigenetic silencing of MSH2 in EPCAM-expressing tissues. However, the clinical significance of deletions confined to the\n                    <jats:italic>EPCAM-MSH2<\/jats:italic>\n                    intergenic region remains uncertain without in-depth investigation.\n                  <\/jats:p>\n                  <jats:p>\n                    We investigated a family with a strong history of Lynch syndrome-related cancers in whom diagnostic testing by short-read sequencing identified a heterozygous deletion spanning the\n                    <jats:italic>EPCAM-MSH2<\/jats:italic>\n                    intergenic region that was initially classified as a variant of uncertain significance. The variant was further characterised using long-read Oxford Nanopore sequencing with adaptive sampling and methylation profiling.\n                  <\/jats:p>\n                  <jats:p>\n                    Long-read sequencing defined precise breakpoints, and tumour analysis demonstrated\n                    <jats:italic>MSH2<\/jats:italic>\n                    promoter hypermethylation with complete loss of MSH2 protein expression in the absence of germline promoter methylation. The molecular phenotype closely mirrored the recognised mechanism for 3\u2032-end\n                    <jats:italic>EPCAM<\/jats:italic>\n                    deletions, whereby aberrant\n                    <jats:italic>EPCAM<\/jats:italic>\n                    transcription interferes with\n                    <jats:italic>MSH2<\/jats:italic>\n                    promoter regulation in a tissue-specific manner.\n                  <\/jats:p>\n                  <jats:p>\n                    These findings support reclassification of this variant to likely pathogenic and establish a diagnosis of\n                    <jats:italic>EPCAM<\/jats:italic>\n                    -associated Lynch syndrome. This report provides the first evidence that intergenic\n                    <jats:italic>EPCAM-MSH2<\/jats:italic>\n                    deletions are associated with\n                    <jats:italic>MSH2<\/jats:italic>\n                    epimutations and highlights the diagnostic utility of long-read sequencing for noncoding structural variants.\n                  <\/jats:p>","DOI":"10.1136\/jmg-2026-111541","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T17:20:36Z","timestamp":1780680036000},"page":"591-595","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a novel intergenic\n                    <i>EPCAM-MSH2<\/i>\n                    deletion causing EPCAM-associated Lynch syndrome by long-read nanopore sequencing"],"prefix":"10.1136","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4443-2596","authenticated-orcid":false,"given":"Luiza","family":"Steffens Reinhardt","sequence":"first","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Coster","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"Cancer Detection and Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2149-3556","authenticated-orcid":false,"given":"Sean M","family":"Burnard","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin S","family":"Romanis","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia"},{"name":"Cancer Detection and Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Ziolkowski","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"Cancer Detection and Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordana","family":"Pecenpetelovska","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mathe","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"Cancer Detection and Therapy Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Hedley","sequence":"additional","affiliation":[{"name":"Department of Neurology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki E","family":"Maltby","sequence":"additional","affiliation":[{"name":"Department of Neurology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Lechner- Scott","sequence":"additional","affiliation":[{"name":"Department of Neurology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Ashton","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A","family":"Avery-Kiejda","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney J","family":"Scott","sequence":"additional","affiliation":[{"name":"Molecular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia"},{"name":"School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"2026102307200978000_63.9.591.1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-16-0693"},{"key":"2026102307200978000_63.9.591.2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh034"},{"key":"2026102307200978000_63.9.591.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2009.01230.x"},{"key":"2026102307200978000_63.9.591.4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/humu.23688","article-title":"EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome","volume":"40","author":"Pathak","year":"2019","journal-title":"Hum 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improves the characterization of large-scale rearrangement for the diagnosis of cancer predisposition","volume":"15","author":"Chevrier","year":"2025","journal-title":"Clin Transl Med"},{"key":"2026102307200978000_63.9.591.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02024-y"},{"key":"2026102307200978000_63.9.591.17","doi-asserted-by":"crossref","unstructured":"Plazzer JP , Macrae F , Yin X , et al . Mismatch repair gene specifications to the acmg\/amp classification criteria: consensus recommendations from the insight clingen hereditary colorectal cancer \/ polyposis variant curation expert panel. 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