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            <funder>We thank the patients and their families for their participation in this study. Patients included in this study were diagnosed through multiple studies, including PFMG2025; DEFIDIAG, a study sponsored by INSERM and supported by the French Ministry of Health in the framework of French initiative for genomic medicine (PFMG2025); Solve-RD, a project that has received funding from the European Union’s Horizon 2020 research and innovation program (grant 779257); Deutsche Forschungsgemeinschaft (DFG; projects 458099954 (to C. Depienne) and 37144118 (to R.A.J. and S. Neuser)); Inserm as part of the 2022 MESSIDORE program (project Inserm-MESSIDORE 19), and the European Joint Programme on Rare Diseases GENOMIT I6478-B by the Austrian Science Fund FWF and by the Centre for Population Genomics (Garvan Institute of Medical Research and Murdoch Children’s Research Institute), which was funded in part by a Medical Research Future Fund (MRFF) Genomics Health Futures Mission grant (2008820). Part of the results have been supported by the RNU-SPLICE project, financed by the health philanthropic program of Mutuelles AXA, dedicated to supporting innovative research projects in France (to C.N.). Part of this study was supported by the ‘Priority Research Programme on Rare Diseases’ of the French Investments for the Future Programme, project MultiOmixCare. The structural interpretation was conducted by C. Charenton and A.J. as part of the ERC Starting Grant project ‘SPLIFEM’. A.S. received a grant from Region Normandie and GIRCI Nord-Ouest (FHU-A2M2P). This research was made possible through access to data in the National Genomic Research Library, which is managed by GEL (a wholly owned company of the Department of Health and Social Care). We thank P. O’Donovan, M. Sato and Z. Mustafa from GEL for their help with Airlock requests. The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. Cases identified by the Broad Center for Mendelian Genomics (to A.O’D.-L. and S.L.S.) were supported by the National Human Genome Research Institute (grants UM1HG008900 and U01HG0011755). We thank the Care4Rare Canada Consortium for their support of a subset of this work. The Care4Rare Canada Consortium is funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec and the Children’s Hospital of Eastern Ontario Foundation. K.M.B. is supported by a CIHR Foundation (grant FDN-154279) and a Tier 1 Canada Research Chair in Rare Disease Precision Health. G.D.G. is supported by a CIHR Fellowship award (MFE-491710). A.M.I., J.L.L. and R.L. obtained support for sequencing through Translational Implementation of Genomics for Rare Disease, funded by Genome Canada, Genome Alberta, Alberta Innovates and the Alberta Children’s Hospital Foundation. The research at Boston Children’s Hospital was supported by the BCH Children’s Rare Disease Collaborative and the Robinson Fund for Transformative Research in Epilepsy, and A.M.D’G. was supported by a BCH Office of Faculty Development/Basic &amp; Clinical Translational Research Executive Committees Faculty Career Development Fellowship. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. The UDN-Aus acknowledges financial support from the Australian Government’s MRFF (grant MRF2007567). We thank H. Thomson and E. Martin for their contributions to patient data collection in UDN-Aus. Genome sequencing in Spanish patients was supported by the Undiagnosed Rare Diseases Program of Catalonia (PERIS SLT002/16/00174) from the Autonomous Government of Catalonia, the Biomedical Research Networking Center on Rare Diseases (CIBERER, ACCI19-759), the Hesperia Foundation (Royal House of Spain), and La Marató de TV3 Foundation with project 202006-30 and IMPACT-Genomica (IMP/00009) to A.P. T.B.H. received funding from the German Research Foundation (DFG; research grants 418081722, 433158657 and EJP-RD Artemis—542553983) and the European Commission (Recon4IMD—GAP-101080997). We thank the CERCA Program/Generalitat de Catalunya for institutional support. We thank M.D. Biase, A. Wilson, A. Rehman, A. Thomas-Wilson, S. Phadke and A. Vabhyankar from the New York Genome Center for their help with genome analysis and for providing anonymized patient data. We thank A. Lavillaureix, C. Quélin, F. Prieur and F. Demurger for their contribution to the establishment of KTM2A/KTM2D episignatures. This study uses resources generated by the ENCODE Consortium and the T. Gingeras lab (CSHL). N.W. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 220134/Z/20/Z), a research prize from the Lister Institute. Y. Chen is supported by a studentship from Novo Nordisk. P.Z.’s work was supported by Stiftung Michael through the assistance of the Canger-Janz Fellowship. T.S.B. was supported by ZonMw Vidi (grant 09150172110002) and acknowledges support from Stichting 12q. K.Õ. was supported by the Estonian Research Council (grants PRG471 and PRG2040). S.L.S. was supported by a Manton Center for Orphan Disease Research postdoctoral fellowship. S. Baulac received a grant from la Fondation pour la Recherche médicale (EQU202203014861). The Chair in Genomic Medicine awarded to J. Christodoulou is generously supported by The Royal Children’s Hospital Foundation. A. Kuechler, F.J.K., A.R. and G. Vasileiou from Germany, T.S.B. from the Netherlands, K.Õ. from Estonia, A.-S.D.-P., L.F., G.L., J.V.-G., M. Willems and S.O. from France and N.R. from Belgium are members of the European Reference Network (ERN) ITHACA, whose coordinator is A. Verloes. G.L., N.C., L. Januel and Z.G.-S. are members of ERN EpiCARE. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Open access was supported by AP-HP.</funder>
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