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.
Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study
Glazer, Andrew M. , Davogustto, Giovanni , Shaffer, Christian M., Desai, Reshma R. , Farber‐Eger, Eric , Dikilitas, Ozan , Shang, Ning , Muhammad, Ayesha , Shaffer, Lauren Lee, Kalash, Olivia R., Bland, Harris T. , Yoneda, Zachary T. , Mitchell, Devyn , Kroncke, Brett M. , Jarvik, Gail P. , Gordon, Allan , Larson, Eric B. , Manolio, Teri A. , Luo, Jonathan Z. , Schaid, Daniel J. , Namjou, Bahram , Singhal, Ashutosh , Liu, Cong , Ralston, James D. , Leppig, Kathleen A. , Håkonarson, Håkon , Sleiman, Patrick , Sohn, Sunghwan , Network, the eMERGE, Denny, Joshua C. , Wei, Wei‐Qi, Shoemaker, M. Benjamin , Roden, Dan M. , Ralston, James D. , Farber-Eger, Eric H , Dikilitas, Ozan , Mosley, Jonathan D , Van Driest, Sara L , Wells, Quinn S , Wada, Yuko , Yoneda, Zachary T , Kroncke, Brett M , Kullo, Iftikhar J , Jarvik, Gail P , Gordon, Adam S , Manolio, Teri A , Mirshahi, Tooraj , Schaid, Daniel, Alsaied, Tarek , Hripcsak, George , McNally, Elizabeth M , Sohn, Sunghwan , Glessner, Joseph , Wei, Wei-Qi , George, Alfred L , Shoemaker, M Benjamin , Roden, Dan M. , Hakonarson, Hakon , Denny, Joshua C , Bland, Sarah T , Liu, Cong , Glazer, Andrew M , Vanoye, Carlos G. , Pacheco, Jennifer A. , Yang, Tao , Driest, Sara L. Van , Wells, Quinn S. , Wada, Yuko , Kullo, Iftikhar J. , Singh, Rajbir , Weng, Chunhua , McNally, Elizabeth M. , Chung, Wendy K. , Carrell, David , Network, the eMERGE, George, Alfred L.
Circulation | December 21, 2021 | Volume: 145 | Issue: 12 | Pages: 877-891
10.1161/circulationaha.121.055562
Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.