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.
Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3
Schirwani, Schaida , Albaba, Shadi , Carere, Deanna Alexis , Sacoto, María J. Guillen , Zamora, Francisca Milan, Si, Yue , Rabin, Rachel , Renaud, Deborah L. , Hauser, Natalie , Blanchet, Patricia, Foulds, Nichola, Dixit, Abhijit , Fisher, Richard, Armstrong, Ruth, Isidor, Bertrand , Demirdas, Serwet , Dykzeul, Natalie, Cohen, Julie S. , Grand, Katheryn , Swols, Dayna Morel , Albassam, Hessa F., Naik, Swati , Ragge, Nicola , Tedesco, Maria Giovanna , Harrison, Rachel , Bouman, Arjan , Palen, Emily, Challman, Thomas D. , Willemsen, Marjolein H. , Vogt, Julie , Cunniff, Christopher , Bergstrom, Katherine , Bruel, Ange‐Line , Kini, Usha , Alkuraya, Fowzan S. , Slegesky, Valerie, Meeks, Naomi, Girotto, Paula Natale , Johnson, Diana , Study, DDD, Newbury‐Ecob, Ruth , Lynch, Sally Ann , Graham, John M. , Balasubramanian, Meena , Hauser, Natalie , Schrier Vergano, Samantha , Bouman, Arjan , Cunniff, Christopher , Bergstrom, Katherine , Bruel, Ange-Line , Alkuraya, Fowzan S , Prontera, Paolo , Li, Dong , Graham, John M , Zamora, Francisca Millan, Pappas, John , Reid, Evan , Cogné, Benjamin , Vergano, Samantha A. Schrier , Slavotinek, Anne , Naik, Swati, Dean, John , Costa, Cinzia , Walia, Jagdeep Singh , Study, DDD, Ockeloen, Charlotte W. , Li, Dong , Pierson, Tyler Mark
American Journal of Medical Genetics Part A | August 26, 2021 | Volume: 185 | Issue: 11 | Pages: 3446-3458
AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.