{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T06:27:53Z","timestamp":1794119273057,"version":"4.8.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100019559","name":"Carl von Ossietzky Universit\u00e4t Oldenburg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019559","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Congenital heart defects (CHDs) are the most common malformation amongst newborns, with a prevalence of approximately 0.8\u20132%. The etiology of CHD is highly complex and can be linked to genetic and nongenetic factors. The molecular basis remains partially unclear, and only a minority of patients can be assigned to clear monogenic causes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here we analyzed a cohort of 3907 CHD cases and population-matched controls using exome sequencing. In addition, we employed epigenetic profiling on a subset of cases that harbored rare\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 24 pathogenic or likely pathogenic single nucleotide variants (SNVs) in\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      in our exome cohort, as well as a further 15 variants of uncertain significance (VUS) likely to have a deleterious effect. Although the cardiac phenotypes showed some heterogeneity, non-syndromic Tetralogy of Fallot (ToF) and related malformations were the most frequent finding in 56% (22\/39). In particular, missense variants altering cysteine residues involved in forming disulfide bridges were identified, specifically in TOF patients. Altogether,\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -haploinsufficiency represented the most common monogenic cause in our cohort and accounted for an estimated 1% of CHD cases. Combined with additional cases assembled through collaborations, we present 67 individuals with ultrarare variants affecting\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:p>\n                      This prominent role of\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      calls for an accurate and accessible evaluation of variants. To this end we explored DNA methylation testing and successfully established a\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -specific episignature. This signature also displays a robust specificity in relation to 99 other episignatures. Taken together, we found that truncating, splice-altering, as well as missense\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      variants, can generate a distinct DNAm episignature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified that\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -haploinsufficiency variants represented the most common monogenic cause in our cohort and accounted for an estimated 1\u00a0% of CHD cases. Furthermore, we conclude that methylation profiling can contribute to (NOTCH1) variant interpretation and improve the diagnostic management of CHD patients. Lastly, we established a\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      -specific episignature, which represents the first non-syndromic signature, significantly extending the scope of patients that can benefit from methylation analysis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-025-01587-6","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:37:19Z","timestamp":1767767839000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["DNA methylation analysis of NOTCH1 variants reveals the first episignature for non-syndromic congenital heart 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Nucleic Acids Res. 2023;51(D1):D638\u201346.","journal-title":"Nucleic Acids Res"}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-025-01587-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01587-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01587-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:03:42Z","timestamp":1767794622000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13073-025-01587-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1587"],"URL":"https:\/\/doi.org\/10.1186\/s13073-025-01587-6","relation":{},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,7]]},"assertion":[{"value":"9 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the regulations of the Western University Research Ethics Board (REB116108, and REB106302), The Medical Ethical Committee (METC) of the Amsterdam UMC, location AMC (NL48529.018.14). This study was approved under the ethics approval (EA2\/131\/10) Berlin, Germany. We obtained written informed consent from the participants or their substitute decision maker to publish patients\u2019 clinical and genetic information. Institutional Research Ethics Boards of The Hospital for Sick Children, Amsterdam Medical Center, The Children\u2019s Hospital at Westmead and Kompetenznetz Angeborene Herzfehler gave ethics approval for the collection and use of biospecimens through respective registries i.e. The Heart Centre Biobank (Ontario, Canada), CONCOR (Amsterdam, Netherlands), Kids Heart BioBank (Sydney, Australia) and German Heart Registry (Berlin, Germany). Written informed consent to participate was obtained from all patients and\/or their parents\/legal guardians. This study protocols adhered to the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"BS is a shareholder in EpiSign Inc. SM is on the Advisory Board of Bristol Myers Squibb, Rocket Pharmaceuticals, and Tenaya Therapeutics. All other authors declare not to have any competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2"}}