Curation of Epilepsy Sodium Channel Gene Variation – Clingen Expert Panel Consensus
Abstract number :
1.374
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204948
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Stacey Cohen, MS, LCGC – Children's Hospital of Philadelphia; Lacey Smith, MS CGC – Boston Children's Hospital; Shridhar Parthasarathy, BS – Children's Hospital of Philadelphia; Emily Bonkowski, MS CGC – St. Jude Children’s Research Hospital; William Hong, MD – Boston Children's Hospital; Kimberly Wiltrout, MD – Boston Children’s Hospital; Alexander Ing, MS CGC – Lurie Children’s Hospital of Chicago; Andreas Brunklaus, MD – Royal Hospital for Children; Christopher Thompson, PhD – Northwestern University; Jacy Wagnon, PhD- Ohio State University; Brendan Burns, PhD – Illumina; David Lewis-Smith, MD – Newcastle University; Dennis Lal, PhD – Cleveland Clinic; Elizabeth Butler, MS CGC – GeneDx; Jillian McKee, MD PhD – Children's Hospital of Philadelphia; Miriam Meisler, PhD – University of Michigan; Rhonda Lassiter, PhD – Ambry Genetics; Sarah Dugger, CGC, PhD – Invitae Corporation; Samin Sajan, PhD – Illumina; Yanmin Chen, PhD – GeneDx; Katherine Benson, PhD – Royal College of Surgeons in Ireland; Erin Riggs, MS, CGC – Geisinger Health System; Annapurna Poduri, MD, MPH – Boston Children's Hospital; Heather Mefford, MD, PhD – St. Jude Children’s Research Hospital; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale: Disease-causing variants in the epilepsy sodium channel genes (SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B) represent among the most common monogenic causes of pediatric-onset epilepsy. Variants in genes are classified in a five-tier system as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic as described in the American College of Medical Genetics (ACMG) consensus guidelines in Richards et al 2015. These classifications are essential for proper diagnosis and ultimately eligibility for gene-specific epilepsy therapies. However, the current general classification criteria do not fully capture the properties unique to this set of genes. In our study, we aimed to refine variant interpretation classification guidelines to make them more specific to the epilepsy sodium channel genes.
Methods: We established the Clinical Genome Resource (ClinGen) Epilepsy Sodium Channel Variant Curation Expert Panel within the Neurodevelopmental Disorders Clinical Domain Working Group (CDWG). The group is comprised of a group of experts and curators from clinic, academia, and industry who review existing variant classification guidelines per ACMG and ClinGen as well as relevant medical literature to establish consensus guidelines for variant classification of the genes of interest.
Results: We created a revised set of variant classification guidelines for the epilepsy-related sodium channel genes (SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B) based on those described in Richards et al 2015, updated ClinGen guidance, and gene specific information. These guidelines include most notably specifications for phenotypic specificity, population frequency, mutational hotspots, paralogous gene information, and recommendations for inclusion of electrophysiological functional assays.
Conclusions: Classification of variants in epilepsy-related sodium channel genes can be refined in a formal framework to include gene specific information. This updated framework will be incorporated into variant classification in the clinical laboratory setting, which will be essential for proper diagnosis of the associated disorders and eventual eligibility for gene-specific trials and therapies.
Funding: This work was supported by a National Institutes of Health grant (U24NS120854-01).
Genetics