Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy

Gregory Costain; Dawn Cordeiro; Diana Matviychuk; Saadet Mercimek-Andrews

doi:10.1016/j.neuroscience.2019.08.016

Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy

Neuroscience. 2019 Oct 15:418:291-310. doi: 10.1016/j.neuroscience.2019.08.016. Epub 2019 Sep 2.

Authors

Gregory Costain¹, Dawn Cordeiro², Diana Matviychuk³, Saadet Mercimek-Andrews⁴

Affiliations

¹ Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Medical Genetics and Genomics Residency Training Program, University of Toronto, Toronto, Ontario, Canada.
² Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. Electronic address: saadet.andrews@sickkids.ca.

PMID: 31487502
DOI: 10.1016/j.neuroscience.2019.08.016

Abstract

Genetic diagnosis of childhood epilepsy is crucial to provide disease-specific treatments. This report describes the genetic landscape of childhood epilepsy revealed by targeted next-generation sequencing panels for epilepsy (TNGSP-E) and whole exome sequencing (WES). In this retrospective cohort study, TNGSP-E and/or WES were applied to identify underlying genetic diagnoses in children seen in a single Pediatric Epilepsy Genetics Clinic. We reviewed electronic patient charts for phenotypes and biochemical, genetic, and neuroimaging investigations. Forty-four different genetic diagnoses were confirmed in 71 of 197 patients (36%; 95% CI 29.3%-43.2%). The diagnostic yield of WES (37%) was 1.9-fold greater than the diagnostic yield of TNGSP-E (19.0%; P=.0018). The number of genes included in TNGSP-E was not correlated with whether or not the test resulted in a diagnosis (Pearson's R=-0.02, P=.8). Inherited metabolic disorders accounted for 13% of the genetic diagnoses, despite abnormal metabolic investigations being an exclusion criteria. There was a direct treatment implication in 6% of patients with inherited metabolic disorders including pyridoxine dependent epilepsy, glucose transporter 1 deficiency and neuronal ceroid lipofuscinosis type 2. Additionally, there might be some treatment implications in 30% of patients with genetic diagnoses including SCN1A, SCN2A, SCN8A, and KCNQ2 associated epilepsies by application of effective anti-epileptic drugs or the ketogenic diet therapy. The high diagnostic yield of clinical molecular genetic investigations and their disease-specific treatment implications highlight the importance of genetic diagnosis in childhood epilepsy. We recommend a stepwise diagnostic algorithm including metabolic investigations for treatable disorders, chromosomal microarray analysis, TNGSP-E, and WES.

Keywords: Epilepsy; Epileptic encephalopathy; Global developmental delay; Movement disorder; Targeted next-generation sequencing panels for epilepsy; Whole exome sequencing.

MeSH terms

Brain Diseases, Metabolic / genetics
Child
Child, Preschool
Cohort Studies
Epilepsy / drug therapy*
Epilepsy / genetics*
Exome Sequencing
Female
High-Throughput Nucleotide Sequencing
Humans
Infant
Male
Mutation / genetics
Phenotype
Retrospective Studies