Citations 2
Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification
Brünger, Tobias , Krey, Ilona , Kim, Suyeon, Klöckner, Chiara , Myers, Scott J, Johannesen, Katrine M. , Stefanski, Arthur , Taylor, Gary, Macnee, Marie , Dahl, Rebekka S., Yuan, Hongjie, Kim, Sukhan, Helbig, Ingo, Pan, Jen, Kurganov, Erkin , Baez, David, Zuberi, Sameer M., Lerche, Holger, May, Patrick, Ivaniuk, Alina, Meskis, Mary Anne , Hood, Veronica , Schust, Leah F., Freed, Amber, Froelich, Steven, Deng, Alexander T., Bouman, Arjan , Hajianpour, M.J. , Pal, Deb K. , Danvoye, Leslie, Lederer, Damien , BALCI, TUĞÇE, Hagebeuk, Eveline , Heidlebaugh, Alexis R. , Oetjens, Kathryn F., Striano, Pasquale, Williams, Sarah Drewes, Engelen, Kalene van , Howell, Katherine B. , Khoury, Jean , Benke, Tim A., Strehlow, Vincent , Platzer, Konrad, Ramsey, Amy J, Manaster, Lisa, Malepati, Sunitha, Fox, Pangkong M., Noebels, Jeffrey, Chung, Wendy, Poduri, Annapurna, Stripe, Laina Lusk, Ruggiero, Sarah M., Cohen, Stacey, Wilmarth, Olivia, Prentice, Anna Jenne, Cha, Esther, Budnik, Nikita , Kramer, Audra A. , Gh, Zhang, Palotie, Aarno, Daly, Mark J., Møller, R., Lemke, Johannes R., Lal, Dennis , Møller, Rikke S. , May, Patrick , Bruenger, Tobias , Pan, Jen Q , Farrant, Mark , Wyllie, David J A , Bosselmann, Christian , Mantegazza, Massimo , May, Patrick , Ivaniuk, Alina , Goodspeed, Kimberly , Trinidad, Marena , Aledo-Serrano, Ángel , Pal, Deb K , Platzer, Konrad , Ruggiero, Sarah M , Daly, Mark J. , George, Alfred L , Brunklaus, Andreas , Møller, Rikke S , Myers, Scott J. , Taylor, Gary, Pérez‐Palma, Eduardo , Schorge, Stéphanie , Dahl, Rebekka S. , Perszyk, Riley E. , Bajaj, Sunanjay , Helbig, Ingo , Wollmuth, Lonnie P. , Báez-Nieto, David , Zuberi, Sameer M. , Boßelmann, Christian M. , Mantegazza, Massimo , Cestèle, Sandrine , Ivaniuk, Alina , Kang, Jing‐Qiong , Gati, Cornelius , Montanucci, Ludovica , Wüster, Arthur , Deng, Alexander T. , Borovikov, Artem O. , Sharkov, Artem A. , Bouman, Arjan , Hoffman, Trevor L. , Howell, Katherine B. , Benke, Tim A. , Platzer, Konrad , Ramsey, Amy J. , Fox, Pangkong , Noebels, Jeffrey L. , Chung, Wendy K. , Poduri, Annapurna , Lusk, Laina G. , Cohen, Stacey , Smith, Lacey A. , Boesch, Sylvia , Prentice, Anna Jenne , Hommersom, Marina P. , Vanoye, Carlos G. , Nothnagel, Michael , Palotie, Aarno V. , George, Alfred L. , Zárate, Yuri A. , Brunklaus, Andreas , Traynelis, Stephen F. , Lemke, Johannes R.
No container title available | March 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.
Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders
O’Grady, Lauren , Vergano, Samantha A. Schrier , Hoffman, Trevor L. , Sarco, Dean, Cherny, Sara , Bryant, Emily , Schultz‐Rogers, Laura , Sacharow, Stephanie , Immken, LaDonna, Holder, Susan, Blackwell, Rebecca R., Buchanan, Catherine A., Yusupov, Roman, Lecoquierre, François , Guerrot, Anne‐Marie , Rodan, Lance H. , Vries, Bert B.A. de , Kamsteeg, Erik Jan, Palomares‐Bralo, María , Brown, Natasha J. , Klee, Eric W. , Babovic‐Vuksanovic, Dusica , Rhodes, Lindsay, Person, Richard, Begtrup, Amber, Keller‐Ramey, Jennifer, Santiago‐Sim, Teresa, Schnur, Rhonda E. , Gold, Nina B. , Schrier Vergano, Samantha , Lecoquierre, Francois , Rodan, Lance , de Vries, Bert B A , Santos Simarro, Fernando , Palomares-Bralo, Maria , Babovic-Vuksanovic, Dusica, Sweetser, David A , Chung, Wendy K. , Pais, Lynn , Ferrer, Alejandro , Begtrup, Amber Hogart
American Journal of Medical Genetics Part A | May 11, 2022 | Volume: 188 | Issue: 9 | Pages: 2750-2759
Abstract The pre‐mRNA‐processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss‐of‐function variants in PRPF8 . These individuals have clinical features that may represent a new neurodevelopmental syndrome.