Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

Abstract

Background: Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children’s Hospital, London, Ontario, Canada. Methods: Children (birth–18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008–March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. Results: In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Conclusions: Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province.

Genetic testing for the epilepsies: A systematic review

“…Moreover, two patients were diagnosed with KBG syndrome (Online Mendelian Inheritance in Man #148050), which informed surveillance strategies for vision and hearing. 28 Changes in clinical management that did not involve ASMs, such as use of KD, were reported in multiple studies. For example, in a cohort of patients with DEE, robust KD response (>90% seizure reduction) was associated with syndrome molecular diagnosis (p = .005), with significantly more patients with pathogenic mutations in the responder versus the nonresponder group (p = .016).…”

“…3.3.5 | Recurrence risk estimation/ family planning Fifteen publications included some mention of the impact that genetic diagnosis may have on recurrence risk estimation and/or family planning. 14,17,20,23,25,27,28,42,44,45,[48][49][50][51][52] Of note, none of these papers included a description of their methods regarding systematic collection of this type of data. Several papers included discussion regarding the impact of genetic diagnosis on recurrence risk estimation or genetic counseling.…”

Trends and hotspots in gene research of epilepsy in children: A review and bibliometric analysis from 2010 to 2022

“…The results showed that the diagnostic rate of WES was the highest, followed by microarray, single-gene test, and targeted polygenic group test. [55] It is strongly recommended to carry out gene detection for all patients with unexplained epilepsy in the order of exon/genome sequencing and/or multiple genomes (>25 genes), followed by chromosome microarray detection. [42] 4.10.…”

Yield and Utility of Routine Epilepsy Panel Genetic Testing Among Young Patients With Seizures

“…4 It is estimated that about two-thirds of patients diagnosed with epilepsy have a genetic component, which may involve multiple genes as well as interactions with the environment. [4][5][6] More than 1000 epilepsy-related single gene variants have been identified. 6 Genetic syndromes associated with epilepsy include channelopathies such as SCN1A, inborn errors of metabolism such as SLC2A1, or congenital syndromes such as TSC1 and TSC2.…”

“…[10][11][12] Ketogenic diet can be therapeutic in SLC2A1 genetic variation causing GLUT-1 deficiency. 5,10,12,13 Identifying a genetic cause can also trigger screening for certain comorbidities. 1,4,8,14 In a previous study, 48.8% of patients with pathogenic or likely pathogenic genetic testing results underwent changes in clinical management, including appropriate initiation, addition or cessation of antiseizure medications, specialist referrals, and monitoring for comorbidities.…”