SCN Portal for Epilepsy Genetics: Facilitating Genetic Test Interpretation, Research and Education for Sodium Channel Disorders
Abstract number :
3.349
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1826235
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Tobias Brünger, MS - Cologne Center for Genomics, University of Cologne; Eduardo Pérez-Palma - Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana. Santiago, Chile; Katrine Johannesen - Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.; Chiara Klöckner - Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Marie Macnee - Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany; Arthur Stefanski - Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.; Ingo Helbig - Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Sameer Zuberi - The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK. Institute of Health and Wellbeing, University of Glasgow, UK.; Patrick May - Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.; Johannes Lemke - Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Jen Pan - Stanley Center of Psychiatric Research, Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, 02142, MA, USA; Alfred George - Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL USA; Rikke Møller - Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.; Andreas Brunklaus - The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK. Institute of Health and Wellbeing, University of Glasgow, UK.; Dennis Lal - Genomic Medicine Institute & Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA. Stanley Center of Psychiatric Research, Broad Institute of Harvard and MIT, MA, USA
Rationale: Pathogenic variants affecting the voltage-gated sodium channel (SCN) encoding genes SCN1A, SCN2A, SCN3A, and SCN8A cause a spectrum of neurodevelopmental disorders with or without epilepsy. Variant interpretation represents a challenge, even for SCN gene experts. Currently, clinical, genetic, and molecular data about SCN genes are not connected and distributed across registries, databases, and the literature. To overcome current limitations, we developed the SCN-Portal, which contains the largest expert-curated dataset of sodium channel disorders alongside user-friendly analytics and educational resources.
Methods: Presently, we aggregated from 1849 patients with pathogenic variants in SCN1A, SCN2A, SCN3A, and SCN8A published and unpublished clinical and genetic data. We collected and curated electrophysiological data for 425 SCN gene variants from the literature and generated molecular read-outs for additional SCN1A and SCN2A variants. These data were connected with protein structures, and annotated with >40 protein features characterizing the location, physicochemical properties, and interactions of the variants within 3D protein structures. Several annotations, such as those for the size, location, and corresponding physiochemical properties of the pore, are novel and have been calculated using bioinformatic tools. Using our previously developed paralog framework, information from each SCN gene was transferred in silico to the other SCN genes.
Results: We designed the SCN-Portal for three user scenarios: i) Education: We provide a rich source of information in >10 languages for all known SCN1/2/3/8A-related diseases; ii) Access to expert-level variant interpretation: We provide novel expert-curated web applications that enable variant pathogenicity classification and disease trajectory prediction; iii) Research resource: Throughout the SCN-Portal, we provide novel research tools to explore our extensive and unique biomedical data resource. Users will be guided by tutorials with illustrative examples and will not require programming skills.
Conclusions: The SCN-Portal infrastructure is scalable and, with increasing data, may transform variant interpretation, research and education for SCN1A, SCN2A, SCN3A and SCN8A. The SCN-Portal will be hosted at http://scn-portal.broadinstitute.org. We are actively looking for collaborators contributing to this project.
Funding: Please list any funding that was received in support of this abstract.: BMBF Treat-ION grant (01GM1907).
Genetics