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.
Variants in ATP6V0C are associated with Dravet‐like developmental and epileptic encephalopathy
Rong, Marlene , Marques, Paula , Ali, Quratulain Zulfiqar , Morcos, Ricardo , Chandran, Ilakkiah , Qaiser, Farah , Møller, Rikke S. , Bayat, Allan , Rubboli, Guido , Gardella, Elena , Reuter, Miriam S. , Sands, Tristan T. , Scheffer, Ingrid E. , Schneider, Amy , Nabbout, Rima , Sullivan, Joseph , Valente, Kette D. , Brunklaus, Andreas , Marques, Paula T , Poduri, Annapurna , Wirrell, Elaine C , Nabbout, Rima , Sullivan, Joseph , Valente, Kette , Auvin, Stéphane , Knupp, Kelly G , Brunklaus, Andreas , Aledo-Serrano, Ángel , Andrade, Danielle M , Rubboli, Guido , Scheffer, Ingrid E , Gardella, Elena , Møller, Rikke S , Bayat, Allan , Wirrell, Elaine , Auvin, Stéphane , Knupp, Kelly G. , Andrade, Danielle M.
Epilepsia | March 14, 2025 | Volume: 66 | Issue: 6 | Pages: 2046-2052
Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .