ArticlemedRxiv : the preprint server for health sciences2026
Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.
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Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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93 authors.
Tobias BrüngerDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0003-2591-432X
Ilona KreyInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Suyeon KimDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Chiara KlöcknerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Scott J MyersDepartment of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Katrine M JohannesenDepartment of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Dianalund, Denmark.ORCID 0000-0002-7356-3109
Arthur StefanskiGenomic Medicine Institute and Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Gary TaylorDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Eduardo Perez-PalmaUniversidad del Desarrollo, Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Santiago de Chile 7610658, Chile.
Marie MacneeCologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.
Stephanie SchorgeDepartment of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Rebekka S DahlDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Hongjie YuanDepartment of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Riley E PerszykDepartment of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Sukhan KimDepartment of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Sunanjay BajajDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Ingo HelbigDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jen Q PanStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.ORCID 0000-0003-0767-086X
Mark FarrantDepartment of Neuroscience, Physiology and Pharmacology, University College London, London, UK.ORCID 0000-0002-9918-0376
Lonnie WollmuthDepartment of Neurobiology & Behavior and Biochemistry & Cell Biology, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY, USA.
David J A WyllieInstitute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.ORCID 0000-0002-4957-6049
Erkin KurganovStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.
David BaezStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.
Sameer ZuberiSchool of Health and Wellbeing and Royal Hospital for Children University of Glasgow, Glasgow, UK.
Christian M BoßelmannDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.ORCID 0000-0002-1596-5599
Holger LercheDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
Massimo MantegazzaUniversité Côte D'azur, CNRS UMR7275, Inserm U1323, Institute of Molecular and Cellular Pharmacology, Valbonne - Sophia Antipolis, France.ORCID 0000-0002-1070-7929
Sandrine CestèleUniversité Côte D'azur, CNRS UMR7275, Inserm U1323, Institute of Molecular and Cellular Pharmacology, Valbonne - Sophia Antipolis, France.
Patrick MayLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.ORCID 0000-0001-8698-3770
Alina IvaniukDepartment of Neurology, Mayo Clinic in Florida, Jacksonville, Fl, 32224, USA.ORCID 0000-0001-9912-3112
Mary Anne MeskisDravet Syndrome Foundation, Cherry Hill, NJ, USA.
Veronica HoodDravet Syndrome Foundation, Cherry Hill, NJ, USA.
Leah SchustFamilieSCN2A Foundation 501(c)(3), Gettysburg, PA, USA.
Kimberly GoodspeedDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID 0000-0002-8823-2839
Jing-Qiong KangVanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
Amber FreedSLC6A1 Connect, 1939 Temperence Hill Drive, Frisco, TX 75034, USA.
Cornelius GatiDepartment of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.
Ludovica MontanucciDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Arthur WusterBioMarin Pharmaceutical Inc., Novato, CA, USA.
Marena TrinidadInnovative Genomics Institute, University of California, Berkeley, CA, USA, 94720.ORCID 0000-0001-7839-4642
Steven FroelichBioMarin Pharmaceutical Inc., Novato, CA, USA.
Alexander T DengNHS South East Genomic Medicine Service, Guy's and St Thomas's NHS Foundation Trust, London SE1 9RT, UK.
Ángel Aledo SerranoEpilepsy Program, Neurology Department, Hospital Ruber Internacional, Madrid 28034, Spain.ORCID 0000-0003-4889-3365
Artem BorovikovResearch and Counseling Department, Research Centre for Medical Genetics, Moscow 115478, Russia.
Artem SharkovVeltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Russia.
Arjan BoumanDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
M J HajianpourDepartment of Pediatrics, Division of Medical Genetics and Genomics, Albany Medical College, Albany Med Health System, Albany, NY 12208, USA.
Deb K PalDepartment of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London SE58AF, UK.ORCID 0000-0003-2655-0564
Leslie DanvoyeDepartment of Neurology, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels 1200, Belgium.
Damien LedererCentre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Charleroi, Belgium.
Tugce R BalciDepartment of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A3K7, Canada.
Eveline E O HagebeukStichting Epilepsie Instellingen Nederland (SEIN), Department of Pediatric Neurology, Heemstede, The Netherlands.
Alexis HeidlebaughDepartment of Developmental Medicine, Geisinger, Danville, PA 17837, USA.
Kathryn OetjensDepartment of Developmental Medicine, Geisinger, Danville, PA 17837, USA.
Trevor L HoffmanDepartment of Regional Genetics, Anaheim, Southern California Kaiser Permanente Medical Group, CA 92806, USA.
Pasquale StrianoPediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy.
Sarah Drewes WilliamsDivision of Genetic and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
Kalene van EngelenMedical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON N6A5W9, Canada.
Katherine B HowellDepartment of Neurology, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Jean KhouryGenomic Medicine Institute and Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Tim A BenkeDepartment of Pediatrics, Neurology and Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
Vincent StrehlowInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID 0000-0001-6127-6308
Amy RamseyDepartment of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
Lisa ManasterCACNA1A Foundation, Inc., 31 Point Rd, Norwalk, CT 06854, USA.
Sunitha MalepatiCACNA1A Foundation, Inc., 31 Point Rd, Norwalk, CT 06854, USA.
Pangkong FoxCACNA1A Foundation, Inc., 31 Point Rd, Norwalk, CT 06854, USA.
Jeffrey NoebelsBlue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
Wendy ChungDepartment of Neurology, Harvard Medical School, Boston, MA, USA.
Annapurna PoduriDepartment of Neurology, Harvard Medical School, Boston, MA, USA.
Laina Lusk StripeDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sarah M RuggieroDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0002-0834-0750
Stacey CohenDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Lacey SmithEpilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Sylvia BoeschCenter for rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Olivia WilmarthDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Anna Jenne PrenticeDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Esther ChaDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Nikita BudnikThe Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Marina P HommersomDepartment of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen 6500 HB, The Netherlands.
Audra KramerDepartment of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA.
Carlos G VanoyeDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Guo-Qiang ZhangDepartment of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Michael NothnagelCologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.
Aarno PalotieDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Mark J DalyStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.ORCID 0000-0002-0949-8752
Alfred L GeorgeDepartment of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA.ORCID 0000-0002-3993-966X
Yuri A ZarateDivision of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
Andreas BrunklausSchool of Health and Wellbeing and Royal Hospital for Children University of Glasgow, Glasgow, UK.ORCID 0000-0002-7728-6903
Stephen F TraynelisDepartment of Pharmacology and Chemical Biology, and the Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Rikke S MøllerDepartment of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, member of ERN EpiCARE, Dianalund, Denmark.ORCID 0000-0002-9664-1448
Johannes R LemkeInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Dennis LalCologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.
Funding
Implementing a Maternal health and PRegnancy Outcomes Vision for Everyone (IMPROVE)UL1TR002378 · NCATS · EMORY UNIVERSITY · PI Andres J Garcia, Elizabeth O. Ofili · 2017 to 2026
$92.1MProject 3 - Development and investigation of murine models of channelopathy-associated epilepsyU54NS108874 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI VANOYE, CARLOS G. · 2018 to 2022
$12.1MGlutamate receptors and human neurological diseaseR35NS111619 · NINDS · EMORY UNIVERSITY · PI Stephen F Traynelis · 2019 to 2026
$6.6MNMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted TherapyR01HD082373 · NICHD · EMORY UNIVERSITY · PI YUAN, HONGJIE · 2015 to 2025
$3.3MPotentiate Cav3.3 To Treat Cognitive Deficits Associated with Impaired Sleep SpindleRF1MH131719 · NIMH · BROAD INSTITUTE, INC. · PI PAN, JEN QIAN, WEÏWER, MICHEL · 2025 to 2025
$2.1M2/4 The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorderR01MH129722 · NIMH · BROAD INSTITUTE, INC. · PI Mark Joseph Daly · 2022 to 2026
$2.0MPotentiate Cav3.3 To Treat Cognitive Deficits Associated with Impaired Sleep SpindleR01MH131719 · NIMH · BROAD INSTITUTE, INC. · PI PAN, JEN QIAN, WEÏWER, MICHEL · 2022 to 2023
$1.8MSyncroPatch 384 Automated Patch Clamp InstrumentS10MH133644 · NIMH · BROAD INSTITUTE, INC. · PI PAN, JEN QIAN · 2023 to 2023
$600kHuman GRIA variants and neurological diseases: from molecular mechanism to rescue pharmacologyR21MH127404 · NIMH · EMORY UNIVERSITY · PI YUAN, HONGJIE · 2021 to 2022
$430kNCATS NIH HHS UL1 TR002378NICHD NIH HHS R01 HD082373NIMH NIH HHS R01 MH129722NIMH NIH HHS R01 MH131719NIMH NIH HHS R21 MH127404NIMH NIH HHS RF1 MH131719NIMH NIH HHS S10 MH133644NINDS NIH HHS R35 NS111619NINDS NIH HHS U54 NS108874
Abstract
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.
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