Analysis of 20,523 Exome Sequences Identifies Pathogenic Repeat Expansions with Increased Prevalence in Epilepsy
Abstract number :
2.336
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204884
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Mark Bennett, PhD – The Walter and Eliza Hall Institute of Medical Research; Caitlin Bennett, BSc (Hons) – University of Melbourne; Amy Schneider, MGenCouns – University of Melbourne; Kathryn Friend, PhD – SA Pathology; Mark Corbett, PhD – University of Adelaide; Jozef Gécz, PhD – University of Adelaide; Michael Hildebrand, PhD – University of Melbourne; Lynette Sadleir, MD, MBChB – University of Otago; Ingrid Scheffer, MBBS, PhD – University of Melbourne; Samuel Berkovic, MBBS, MD – University of Melbourne; Melanie Bahlo, PhD – Walter and Eliza Hall Institute of Medical Research; Epi25 Collaborative, - – Broad Institute
Rationale: Repeat expansions (REs) are known to cause at least 40 neurological disorders, including seven associated with epilepsy. Current laboratory-based tests to detect REs are expensive and time consuming, however new bioinformatic methods developed by us and others now enable REs to be identified with next-generation sequencing data. The prevalence of pathogenic REs in epilepsy has not previously been systematically investigated. We evaluate the utility of exome sequencing to capture known REs and assess the contribution of REs to epilepsy.
Methods: We searched exome sequencing data for 13,306 individuals with epilepsy from the Epi25 Collaborative and 7,217 controls (sourced from non-neurological disease cohorts) for the presence of known, disease-causing REs using a suite of bioinformatic RE detection methods. We identified consensus REs predicted by multiple bioinformatic methods and compared the prevalence of REs identified in epilepsy with the control cohort and previously reported population rates in randomly ascertained cohorts.
Results: Nearly half (18) of the known, disease-causing REs had sufficient coverage in the exome sequencing data to be assessed for the presence of REs. Unfortunately, the REs that cause familial adult myoclonic epilepsy are in intronic regions not captured by exome sequencing and were unable to be evaluated. We identified 185 REs at eight loci in our epilepsy cohort compared to 73 REs in controls, suggesting an overall increased burden of REs in epilepsy (odds ratio = 1.5, 95% CI 1.2-1.9). The observed prevalence of REs at these loci was higher in epilepsy than controls and previously reported population rates. The most frequently observed REs are associated with spinocerebellar ataxia 8, myotonic dystrophy 1 and Huntington’s disease, with 152, 16 and 5 REs observed in epilepsy and odds ratios (95% CI) of 1.5 (1.1-2.1), 2.2 (0.7-9.1) and 1.6 (0.2-74), respectively.
Conclusions: We performed a large-scale analysis to assess the prevalence of known REs in epilepsy. We demonstrated the ability to identify pathogenic REs using exome sequencing data, increasing the clinical utility of this technology. We observed a higher prevalence in epilepsy of pathogenic REs associated with other neurological disorders compared to non-neurological controls or previously reported rates for randomly ascertained cohorts, suggesting that these REs may contribute to genetic risk for epilepsy. Genome sequencing is needed to evaluate all known REs including those associated with epilepsy.
Funding: This work was supported by CURE Epilepsy, the National Health and Medical Research Council (NHMRC) Australia, the Medical Research Future Fund Australia, and through Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme. Epi25 research at the Broad Institute is part of the Centers for Common Disease Genomics program funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute.
Genetics