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Clinical Implementation and Outcomes of Genetic Testing for Epilepsy by the Ontario Epilepsy Genetic Testing Program

Published online by Cambridge University Press:  14 April 2025

Tugce B. Balci Open the ORCID record for Tugce B. Balci [Opens in a new window] ,
Laila C. Schenkel Open the ORCID record for Laila C. Schenkel [Opens in a new window] ,
Cassandra Rastin ,
Kevin Jones Open the ORCID record for Kevin Jones [Opens in a new window] ,
Lysa Boissé Lomax ,
Jacob Turowec ,
Jennifer Kerkhof ,
Pratibha Bhai ,
Olga Jarinova  and
Stacy Hewson
...Show all authors
Tugce B. Balci
Affiliation:
Division of Genetics, Department of Paediatrics, Western University, London, ON, Canada Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada
Laila C. Schenkel
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
Cassandra Rastin
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
Kevin Jones
Affiliation:
Division of Pediatric Neurology Department of Pediatrics McMaster University, Hamilton, ON, Canada
Lysa Boissé Lomax
Affiliation:
Division of Neurology Department of Medicine Queen’s University, Kingston, ON, Canada
Jacob Turowec
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
Jennifer Kerkhof
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
Pratibha Bhai
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
Olga Jarinova
Affiliation:
Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada Department of Genetics, CHEO, Ottawa, ON, Canada
Stacy Hewson
Affiliation:
Department of Genetic Counselling, The Hospital for Sick Children, Toronto; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
A. Narayan Prasad
Affiliation:
Clinical Neurological Sciences, Department of Pediatrics, Western University London, ON, Canada
O. Carter Snead III
Affiliation:
Department of Paediatrics, University of Toronto, Toronto, ON, Canada
David A. Dyment
Affiliation:
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Bekim Sadikovic*
Affiliation:
Molecular Diagnostics Program and the Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
*
Corresponding author: Bekim Sadikovic; Email: bekim.sadikovic@lhsc.on.ca
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Abstract:

Background:

Epilepsy is a relatively common condition that affects approximately 4–5 per 1000 individuals in Ontario, Canada. While genetic testing is now prevalent in diagnostic and therapeutic care plans, optimal test selection and interpretation of results in a patient-specific context can be inconsistent and provider dependent.

Methods:

The first of its kind, the Ontario Epilepsy Genetic Testing Program (OEGTP) was launched in 2020 to develop clinical testing criteria, curate gene content, standardize the technical testing criteria through a centralized testing laboratory, assess diagnostic yield and clinical utility and increase genetics literacy among providers.

Results:

Here we present the results of the first two years of the program, demonstrating the overall 20.8% diagnostic yield including pathogenic sequence and copy number variation detected by next-generation sequencing panels. Routine follow-up testing of family members enabled the resolution of ambiguous findings. Post-test outcomes were collected as reported by the ordering clinicians, highlighting the clinical benefits of genetic testing.

Conclusion:

This programmatic approach to genetic testing in epilepsy by OEGTP, together with engagement of clinical and laboratory stakeholders, provided a unique opportunity to gather insight into province-wide implementation of a genetic testing program.

Résumé

RÉSUMÉ

L’Ontario Epilepsy Genetic Testing Program : mise en œuvre clinique du programme et résultats des tests génétiques, relatifs à l’épilepsie

Contexte :

L’épilepsie est une maladie relativement fréquente, qui touche environ 4 – 5 personnes pour 1000, en Ontario, au Canada. Bien que les tests génétiques soient aujourd’hui d’usage courant dans les plans de soins de diagnostic et de traitement, la sélection optimale des tests et l’interprétation des résultats peuvent varier selon les patients et dépendre des fournisseurs de soins.

Méthode :

Premier en son genre en Ontario, le programme Ontario Epilepsy Genetic Testing Program (OEGTP) a été lancé en 2020 afin d’établir des critères de tests cliniques, d’organiser le contenu génétique, d’uniformiser les critères de tests techniques par l’intermédiaire d’un laboratoire central d’analyse, d’évaluer le rendement diagnostique et l’utilité clinique des tests et d’améliorer la compétence informationnelle en génétique chez les fournisseurs de soins.

Résultats :

D’après les résultats ici présentés, obtenus au cours des deux premières années du programme, le rendement diagnostique global est de 20,8 %; il comprend notamment les variations des séquences pathogènes et du nombre de copies détectées par les panels de séquençage de nouvelle génération. Par ailleurs, les tests de suivi courants, effectués parmi les membres des familles touchées, ont permis de résoudre des résultats équivoques. Enfin, les résultats post-tests recueillis comme ils avaient été déclarés par les médecins prescripteurs ont fait ressortir les avantages cliniques des tests génétiques.

Conclusion :

L’approche programmatique des tests génétiques relatifs à l’épilepsie, élaborée dans le cadre de l’OEGTP, en collaboration avec des intervenants cliniques et de laboratoire, a été l’occasion unique de rassembler de l’information sur la mise en œuvre d’un programme de tests génétiques à la grandeur de la province.

Keywords

diagnosticsepilepsynext-generation sequencing
Type
Original Article
Information
Canadian Journal of Neurological Sciences , First View , pp. 1 - 12
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation

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Footnotes

Both Dr Balci and Dr Schenkel had equal contribution as first authors.

References

Bowen, JM, Snead, OC, Chandra, K, Blackhouse, G, Goeree, R. Epilepsy care in Ontario: an economic analysis of increasing access to epilepsy surgery. Ont Health Technol Assess Ser. 2012;12(18):1–41.Google Scholar
Ng, R, Maxwell, CJ, Yates, EA, et al. Brain disorders in Ontario: prevalence, incidence and costs from health administrative data. Institute for Clinical Evaluative Sciences. 2015.Google Scholar
Myers, KA, Johnstone, DL, Dyment, DA. Epilepsy genetics: current knowledge, applications, and future directions. Clin Genet. 2019;95(1):95–111.Google Scholar
Myers, CT, Mefford, HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91.Google Scholar
Demos, M, Guella, I, DeGuzman, C, et al. Diagnostic yield and treatment impact of targeted exome sequencing in early-onset epilepsy. Front Neurol. 2019;10:434.Google Scholar
Vears, DF, Dunn, KL, Wake, SA, Scheffer, IE. It’s good to know”: experiences of gene identification and result disclosure in familial epilepsies. Epilepsy Res. 2015;112:64–71.Google Scholar
Sheidley, BR, Malinowski, J, Bergner, AL, et al. Genetic testing for the epilepsies: a systematic review. Epilepsia. 2022;63(2):375–387.Google Scholar
Costain, G, Cordeiro, D, Matviychuk, D, Mercimek-Andrews, S. Clinical application of targeted next-generation sequencing panels and whole exome sequencing in childhood epilepsy. Neuroscience. 2019;418:291–310.Google Scholar
Leduc-Pessah, H, White-Brown, A, Hartley, T, Pohl, D, Dyment, DA. The benefit of multigene panel testing for the diagnosis and management of the genetic epilepsies. Genes. 2022;13(5):872.Google Scholar
Lee, S, Karp, N, Zapata-Aldana, E, et al. Genetic testing in children with epilepsy: report of a single-center experience. Can J Neurol Sci. 2021;48(2):233–244.Google Scholar
Helbig, I, Riggs, ER, Barry, CA, et al. The clinGen epilepsy gene curation expert panel-bridging the divide between clinical domain knowledge and formal gene curation criteria. Hum Mutat. 2018;39(11):1476–1484.Google Scholar
Dyment, DA, Prasad, AN, Boycott, KM, et al. Implementation of epilepsy multigene panel testing in Ontario, Canada. Can J Neurol Sci. 2020;47(1):61–68.Google Scholar
Jain, P, Andrade, D, Donner, E, et al. Development of criteria for epilepsy genetic testing in Ontario, Canada. Can J Neurol Sci. 2019;46(1):7–13.Google Scholar
Arora, S, Thornton, K, Murata, G, et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med. 2011;364(23):2199–2207.Google Scholar
Kerkhof, J, Rastin, C, Schenkel, L, Lin, H, Sadikovic, B. Clinical validation of a single NGS targeted panel pipeline using the KAPA hyperChoice system for detection of germline, somatic and mitochondrial sequence and copy number variants. Expert Rev Mol Diagn. 2023;23(9):827–841.Google Scholar
Schenkel, LC, Kerkhof, J, Stuart, A, et al. Clinical next-generation sequencing pipeline outperforms a combined approach using sanger sequencing and multiplex ligation-dependent probe amplification in targeted gene panel analysis. J Mol Diagn. 2016;18(5):657–667.Google Scholar
Kerkhof, J, Schenkel, LC, Reilly, J, et al. Clinical validation of copy number variant detection from targeted next-generation sequencing panels. J Mol Diagn. 2017;19(6):905–920.Google Scholar
Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424.Google Scholar
Mercimek-Mahmutoglu, S, Patel, J, Cordeiro, D, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56(5):707–716.Google Scholar
Møller, RS, Larsen, LHG, Johannesen, KM, et al. Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol. 2016;7(4):210–219.Google Scholar
Carvill, GL, Heavin, SB, Yendle, SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–830.Google Scholar
Burk, KC, Kaneko, M, Quindipan, C, et al. Diagnostic yield of epilepsy-genes sequencing and chromosomal microarray in pediatric epilepsy. Pediatr Neurol. 2024;150:50–56.Google Scholar
Miller, DT, Adam, MP, Aradhya, S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–764.Google Scholar
Manickam, K, McClain, MR, Demmer, LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029–2037.Google Scholar
Sánchez Fernández, I, Gaínza-Lein, M, Lamb, N, Loddenkemper, T. Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus. Neurology. 2019;92(20):e2339–e2348.Google Scholar
Bhai, P, Levy, MA, Rooney, K, et al. Analysis of sequence and copy number variants in Canadian patient cohort with familial cancer syndromes using a unique next generation sequencing based approach. Front Genet. 2021;12:698595.Google Scholar
Levy, MA, Kerkhof, J, Belmonte, FR, et al. Validation and clinical performance of a combined nuclear-mitochondrial next-generation sequencing and copy number variant analysis panel in a Canadian population. Am J Med Genet A. 2021;185(2):486–499.Google Scholar
Volodarsky, M, Kerkhof, J, Stuart, A, et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021;58(4):284–288.Google Scholar
Alter, AS, Engelstad, K, Hinton, VJ, et al. Long-term clinical course of Glut1 deficiency syndrome. J Child Neurol. 2015;30(2):160–169.Google Scholar
Wirrell, E, Tinuper, P, Perucca, E, Moshé, SL. Introduction to the epilepsy syndrome papers. Epilepsia. 2022;63(6):1330–1332.Google Scholar
Wirrell, EC, Laux, L, Franz, DN, et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia. 2013;54(9):1595–1604.Google Scholar
Pisano, T, Numis, AL, Heavin, SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56(5):685–691.Google Scholar
Sands, TT, Balestri, M, Bellini, G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. 2016;57(12):2019–2030.Google Scholar
Helbig, KL, Farwell Hagman, KD, Shinde, DN, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18(9):898–905.Google Scholar
LaFlamme, CW, Rastin, C, Sengupta, S, et al. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement. Nat Commun. 2024;15(1):6524.Google Scholar
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