| Title: |
Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification |
| Authors: |
Brünger, Tobias; Krey, Ilona; Kim, Suyeon; Klöckner, Chiara; Myers, Scott J. A.; Johannesen, Katrine M.; Stefanski, Arthur; Taylor, Gary; Perez-Palma, Eduardo; Macnee, Marie; Schorge, Stephanie; Dahl, Rebekka S.; Yuan, Hongjie; Perszyk, Riley E.; Kim, Sukhan; Bajaj, Sunanjay; Helbig, Ingo; Pan, Jen Q.; Farrant, Mark; Wollmuth, Lonnie; Wyllie, David J. A.; Kurganov, Erkin; Baez, David; Zuberi, Sameer; Boßelmann, Christian M.; Lerche, Holger; Mantegazza, Massimo; Cestèle, Sandrine; MAY, Patrick; Ivaniuk, Alina; Meskis, Mary Anne; Hood, Veronica; Schust, Leah; Goodspeed, Kimberly; Kang, Jing-Qiong; Freed, Amber; Gati, Cornelius; Montanucci, Ludovica; Wuster, Arthur; Trinidad, Marena; Froelich, Steven; Deng, Alexander T.; Aledo-Serrano, Ángel; Borovikov, Artem; Sharkov, Artem; Bouman, Arjan; Hajianpour, MJ; Pal, Deb K.; Danvoye, Leslie; Lederer, Damien; Balci, Tugce R.; Hagebeuk, Eveline E. O.; Heidlebaugh, Alexis; Oetjens, Kathryn; Hoffman, Trevor L.; Striano, Pasquale; Williams, Sarah Drewes; van Engelen, Kalene; Howell, Katherine; Khoury, Jean; Benke, Tim A.; Strehlow, Vincent; Platzer, Konrad; Ramsey, Amy; Manaster, Lisa; Malepati, Sunitha; Fox, Pangkong; Noebels, Jeffrey; Chung, Wendy; Poduri, Annapurna; Stripe, Laina Lusk; Ruggiero, Sarah M.; Cohen, Stacey; Smith, Lacey; Boesch, Sylvia; Wilmarth, Olivia; Prentice, Anna Jenne; Cha, Esther; Budnik, Nikita; Hommersom, Marina P.; Kramer, Audra; Vanoye, Carlos G.; Zhang, Guo-Qiang; Nothnagel, Michael; Palotie, Aarno; Daly, Mark J.; George, Alfred L.; Zarate, Yuri A.; Brunklaus, Andreas; Traynelis, Stephen F.; Møller, Rikke S.; Lemke, Johannes R.; Lal, Dennis |
| Contributors: |
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) |
| Publication Year: |
2026 |
| Collection: |
University of Luxembourg: ORBilu - Open Repository and Bibliography |
| Subject Terms: |
Variant classification; Rare Mendelian disorders; ACMG; Human health sciences; Life sciences; Genetics & genetic processes; Sciences de la santé humaine; Sciences du vivant; Génétique & processus génétiques |
| Description: |
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. ; U-AGR-8268 - Treat-ION 2 - MAY Patrick ; R-AGR-3917 - Treat-ION_EKUT - KRAUSE Roland ; 3. Good health and well-being |
| Document Type: |
report |
| Language: |
English |
| Relation: |
FNR16394868 - MechEpi-2 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/01/2022-31/12/2024) - Alexander Skupin; https://orbilu.uni.lu/handle/10993/67959; info:hdl:10993/67959; https://orbilu.uni.lu/bitstream/10993/67959/1/2026.03.05.26347086v1.full.pdf |
| DOI: |
10.64898/2026.03.05.26347086 |
| Availability: |
https://orbilu.uni.lu/handle/10993/67959; https://orbilu.uni.lu/bitstream/10993/67959/1/2026.03.05.26347086v1.full.pdf; https://doi.org/10.64898/2026.03.05.26347086 |
| Rights: |
open access ; http://purl.org/coar/access_right/c_abf2 ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.48AEDC22 |
| Database: |
BASE |