[en] Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework's utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Human health sciences: Multidisciplinary, general & others Genetics & genetic processes
Author, co-author :
Brünger, Tobias ; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Krey, Ilona; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,
Kim, Suyeon; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Klöckner, Chiara; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,
Myers, Scott J. A.; Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA,
Johannesen, Katrine M. ; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Dianalund, Denmark.,
Stefanski, Arthur; Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.,
Taylor, Gary; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Perez-Palma, Eduardo; Universidad del Desarrollo, Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Santiago de Chile 7610658, Chile.,
Macnee, Marie; Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.,
Schorge, Stephanie; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.,
Dahl, Rebekka S.; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Yuan, Hongjie; Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA,
Perszyk, Riley E.; Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA,
Kim, Sukhan; Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA,
Bajaj, Sunanjay; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Helbig, Ingo; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,
Pan, Jen Q. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.,
Farrant, Mark ; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.,
Wollmuth, Lonnie; Department of Neurobiology & Behavior and Biochemistry & Cell Biology, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY, USA.,
Wyllie, David J. A. ; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.,
Kurganov, Erkin; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.,
Baez, David; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.,
Zuberi, Sameer; School of Health and Wellbeing and Royal Hospital for Children University of Glasgow, Glasgow, UK.,
Boßelmann, Christian M. ; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.,
Lerche, Holger; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.,
Mantegazza, Massimo ; Université Côte D'Azur, CNRS UMR7275, Inserm U1323, Institute of Molecular and Cellular Pharmacology, Valbonne - Sophia Antipolis, France.,
Cestèle, Sandrine; Université Côte D'Azur, CNRS UMR7275, Inserm U1323, Institute of Molecular and Cellular Pharmacology, Valbonne - Sophia Antipolis, France.,
Gati, Cornelius; Department of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.,
Montanucci, Ludovica; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Wuster, Arthur; BioMarin Pharmaceutical Inc., Novato, CA, USA.,
Trinidad, Marena ; Innovative Genomics Institute, University of California, Berkeley, CA, USA, 94720,
Froelich, Steven; BioMarin Pharmaceutical Inc., Novato, CA, USA.,
Deng, Alexander T.; NHS South East Genomic Medicine Service, Guy's and St Thomas's NHS Foundation Trust, London SE1 9RT, UK,
Borovikov, Artem; Research and Counseling Department, Research Centre for Medical Genetics, Moscow 115478, Russia.,
Sharkov, Artem; Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Russia.,
Bouman, Arjan; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands,
Hajianpour, MJ; Department of Pediatrics, Division of Medical Genetics and Genomics, Albany Medical College, Albany Med Health System, Albany, NY 12208, USA.,
Pal, Deb K. ; Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London SE58AF, UK.,
Danvoye, Leslie; Department of Neurology, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels 1200, Belgium.,
Lederer, Damien; Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Charleroi, Belgium.,
Balci, Tugce R.; Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A3K7, Canada.,
Hagebeuk, Eveline E. O.; Stichting Epilepsie Instellingen Nederland (SEIN), Department of Pediatric Neurology, Heemstede, The Netherlands.,
Heidlebaugh, Alexis; Department of Developmental Medicine, Geisinger, Danville, PA 17837, USA,
Oetjens, Kathryn; Department of Developmental Medicine, Geisinger, Danville, PA 17837, USA,
Hoffman, Trevor L.; Department of Regional Genetics, Anaheim, Southern California Kaiser Permanente Medical Group, CA 92806, USA.,
Striano, Pasquale; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy,
Williams, Sarah Drewes; Division of Genetic and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.,
van Engelen, Kalene; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON N6A5W9, Canada.,
Howell, Katherine; Department of Neurology, Royal Children's Hospital, Melbourne, VIC 3052, Australia,
Khoury, Jean; Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.,
Benke, Tim A.; Department of Pediatrics, Neurology and Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.,
Strehlow, Vincent; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,
Platzer, Konrad ; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,
Ramsey, Amy; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.,
Noebels, Jeffrey; Blue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.,
Chung, Wendy; Department of Neurology, Harvard Medical School, Boston, MA, USA.,
Poduri, Annapurna; Department of Neurology, Harvard Medical School, Boston, MA, USA.,
Stripe, Laina Lusk; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,
Ruggiero, Sarah M. ; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,
Cohen, Stacey; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,
Smith, Lacey; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.,
Boesch, Sylvia; Center for rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria,
Wilmarth, Olivia; Inova Health System, Falls Church, VA, USA,
Prentice, Anna Jenne; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,
Cha, Esther; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.,
Budnik, Nikita; The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,
Hommersom, Marina P.; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen 6500 HB, The Netherlands.,
Kramer, Audra; Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA,
Vanoye, Carlos G.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.,
Zhang, Guo-Qiang; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.,
Nothnagel, Michael; Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.,
Palotie, Aarno; The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,
Daly, Mark J. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.,
George, Alfred L. ; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.,
Zarate, Yuri A.; Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.,
Brunklaus, Andreas ; School of Health and Wellbeing and Royal Hospital for Children University of Glasgow, Glasgow, UK.,
Traynelis, Stephen F.; Department of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA,
Møller, Rikke S. ; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, member of ERN EpiCARE, Dianalund, Denmark.,
Lemke, Johannes R.; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,
Lal, Dennis; Center for Innovation in Health Informatics, Cook Children's Health Care System, Fort Worth, TX, USA
FNR16394868 - MechEpi-2 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/01/2022-31/12/2024) - Alexander Skupin
Name of the research project :
U-AGR-8268 - Treat-ION 2 - MAY Patrick R-AGR-3917 - Treat-ION_EKUT - KRAUSE Roland
Funding text :
Funding for this work was provided by the German Federal Ministry for Education and Research (BMBF, Treat-ION, 01GM1907D) to D.L., T.B., and P.M., by the BMBF (Treat-Ion2, 01GM2210B, 01GM2210A) to P.M and H.L., by the Fonds Nationale de la Recherche in Luxembourg (FNR, Research Unit FOR-2715, INTER/DFG/21/16394868 MechEPI2) to P.M., by the Chilean National Agency for Research and Development to E.P.P., (ANID) Fondecyt grant 1221464 to E.P.P., by the Dravet Syndrome Foundation (grant number, 272016) to D.L, the by NIH NINDS (Channelopathy-Associated Epilepsy Research Center, U54-NS108874) to A.L.G., J.Q.P., C.G.V., I.H., and D.L., the Agence Nationale de la Recherche - France (Initiative of Excellence Universite Cote d'Azur ANR-15-IDEX-01) to SC and MM, 23% the MRC (MR/T002e6/1) to M.F., the CureGRIN Foundation to M.F.by the NIH-NINDS (NS111619 SFT), the NIH-NIMH (MH127404 H.Y), NICHD (HD082373 H.Y), the GRIN2B Foundation (H.Y), GRIN Therapeutics (S.F.T and S.J.M), Austin's Purpose (S.F.T), SFARI (732132 to S.F.T), by the University Research Committee (Emory URC to H.Y), by Imagine, Innovate and Impact (I3) Awards from the Emory University School of Medicine and through the Georgia CTSA NIH award (UL1-TR002378; H.Y), by the National Institute of Health grants S10MH133644 (J.Q.P.), NS108874 (J.Q.P.), MH131719 (J.Q.P.), MH129722-02 (M. D.), and Stanley Center for Psychiatric Research (J.Q.P. and M.D.), and by grants from CACNA1A foundation (J.Q.P.) and the Ladders to Cures Scientific Accelerator of the Broad Institute of MIT and Harvard (J.Q.P.). The CACNA1A Portal development was funded in part by the Chan Zuckerberg Initiative Rare as One grant. A.P. received support for Simons Searchlight by the Simons Foundation.
