DNA methylation analysis of NOTCH1 variants reveals the first episignature for non-syndromic congenital heart defects
We identified that NOTCH1-haploinsufficiency variants represented the most common monogenic cause in our cohort and accounted for an estimated 1 % 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 NOTCH1-specific episignature, which represents the first non-syndromic signature, significantly extending the scope of patients that can benefit from methylation analysis.
Authors
- David S. Winlaw (ORCID: https://orcid.org/0000-0001-8005-3361)
- Marcel M. A. M. Mannens (ORCID: https://orcid.org/0000-0001-7137-119X)
- Brigitte Stiller (ORCID: https://orcid.org/0000-0002-7657-4647)
- Niels Vos (ORCID: https://orcid.org/0000-0001-6001-3426)
- Robert B. Russell (ORCID: https://orcid.org/0000-0002-7213-1398)
- Thomas Pickardt (ORCID: https://orcid.org/0000-0003-0019-6325)
- Gregor Dombrowsky (ORCID: https://orcid.org/0000-0003-2591-2682)
- Peter Henneman (ORCID: https://orcid.org/0000-0003-2179-7808)
- Liselot van der Laan (ORCID: https://orcid.org/0000-0002-7800-8665)
- Alex V. Postma (ORCID: https://orcid.org/0000-0003-4874-2487)
- Seema R. Mital (ORCID: https://orcid.org/0000-0002-7643-4484)
- Robert Lesurf (ORCID: https://orcid.org/0000-0001-7095-1491)
- Sabine Klaassen
- Anselm Uebing (ORCID: https://orcid.org/0000-0001-8504-0228)
- Anna Wilsdon (ORCID: https://orcid.org/0000-0003-2686-1039)
- Michaël Levy (ORCID: https://orcid.org/0000-0003-2766-5777)
- Ulrike Bauer (ORCID: https://orcid.org/0000-0002-6317-3609)
- Jiao Wang (ORCID: https://orcid.org/0000-0002-4998-8748)
- Felix Berger (ORCID: https://orcid.org/0000-0002-2826-1363)
- Anjali Jain (ORCID: https://orcid.org/0000-0001-6865-8632)
- Hans-Heiner Kramer
- Hashim Abdul-Khaliq
- Ingo Dähnert
- Siobhan Loughna
- Bekim Sadikovic
- Connie R. Bezzina
- Frances Bu’Lock
- Sven Dittrich
- Enrique Audain
- J. David Brook
- Marc-Phillip Hitz
- Mary Ann Thomas
- Ananília Silva
- Jeroen Breckpot
- Almuth Caliebe
Institutions
- Western University (CA)
- Carl von Ossietzky Universität Oldenburg (DE)
- University of Nottingham (GB)
- University of Calgary (CA)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Toronto (CA)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- London Health Sciences Centre (CA)
- Hospital for Sick Children (CA)
- Glenfield Hospital (GB)
- Universitätsklinikum Erlangen (DE)
- Deutsches Herzzentrum der Charité (DE)
- University Hospital Schleswig-Holstein (DE)
- Leipzig Heart Institute (DE)
- Lurie Children's Hospital (US)
- German Centre for Cardiovascular Research (DE)
- Universitäts-Herzzentrum Freiburg-Bad Krozingen (DE)
- SickKids Foundation (CA)
- Deutsches Herzzentrum München (DE)
- Amsterdam University Medical Centers (NL)
- Charité - Universitätsmedizin Berlin (DE)
- Heidelberg University (US)
- University of Amsterdam (NL)
- Saarland University (DE)
- University of Lübeck (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Genome Medicine
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1186/s13073-025-01587-6
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Deutsches Zentrum für Herz-Kreislaufforschung
- Bundesministerium für Bildung und Forschung
- KU Leuven
- Radboud Universitair Medisch Centrum
- Alliance de recherche numérique du Canada