Abstracts

Conserved Variant Pathogenicity and Genotype-phenotype Pattern Across SCN1A, SCN2A, SCN3A and SCN8A Disorders

Abstract number : 2.337
Submission category : 12. Genetics / 12A. Human Studies
Year : 2022
Submission ID : 2204942
Source : www.aesnet.org
Presentation date : 12/4/2022 12:00:00 PM
Published date : Nov 22, 2022, 05:27 AM

Authors :
Tobias Bruenger, MS – University Cologne, Germany; Eduardo Pérez-Palma, PhD – Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana. Santiago, Chile; Ludovica Montanucci, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Marie Macnee, MS – Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany; Alina Ivaniuk, MD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Chiara Klöckner, MD – Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Arthur Stefanski, MS – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Nisha Bhattarai, PhD – Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Johannes Lemke, MD – Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Ingo Helbig, MD – 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.; Stephanie Schorge, PhD – Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK; Patrick May, PhD – Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Andreas Brunklaus, MD – The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK. Institute of Health and Wellbeing, University of Glasgow, UK.; Rikke Møller, PhD – Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.; Dennis Lal, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA

This abstract has been invited to present during the Genetics & Behavior/Neuropsychology/Language platform session

Rationale: Genetic variants in SCN1A, SCN2A, SCN3A, and SCN8A have been associated with heterogeneous types of neurodevelopmental disorders (NDDs) with or without seizures. Adding to the complexity, among patients with clinically similar phenotypes and variants in the same gene, the molecular disease mechanisms associated with the genetic variant can be different, even opposing. As a result, incomplete knowledge of genotype-molecular phenotype associations challenges the safe enrollment of patients in upcoming precision medicine clinical trials. We hypothesize that a comparative analysis of variant localization on a 3-dimensional protein structure can identify correlations between specific phenotypes within and across paralogous sodium channel (SCN) genes.

Methods: We aggregated large expert-curated genetic variant datasets, available molecular functional readouts and applied bioinformatics and data science approaches to identify conserved genotype-phenotype patterns within the SCN gene family.

Results: We aggregated a set of 1,871 patient variants that were expert classified in eleven epilepsy and neurodevelopmental disorder types as well as 2,214 population variants in SCN1A, SCN2A, SCN3A, and SCN8A. We show that pathogenic variants were ~10 fold enriched over population variants at i) conserved residues in the gene family, ii) at positions where in a paralogous gene another patient variant has been reported and iii) in patient variant dense regions. We observed that the phenotype of patients across SCN1A, SCN2A, SCN3A, and SCN8A were correlated for missense variants that were located at analogous residues across different genes. For example, we observed a significant variant colocalization between variants associated with SCN1A-Dravet, SCN2A-autism, and SCN8A-neurodevelopmental disorder without seizures. We show that the eleven SCN1/2/3/8A associated phenotypes clustered into two major and four minor correlated phenotype groups. Presence of a missense variant matching a patient variant from the same phenotype group increases the probability of a variant’s pathogenicity up to 68-fold. Finally, we developed the SCN-Portal (scn-portal.broadinstitute.org) a publicly available resource with a user-friendly interface design to make the full set of results interactively available.

Conclusions: We identified conserved genotype-phenotype patterns across voltage-gated sodium channel genes and show that this information can enhance variant pathogenicity classification and potentially support inferences on molecular disease mechanisms.

Funding: Funding for this work was provided from the German Federal Ministry for Education and Research (BMBF, Treat-ION, 01GM1907D) to D.L., T.B., and P.M.
Genetics