Genomic testing in pediatric epilepsy

Abstract

Genomic testing has become routine in the diagnosis and management of pediatric patients with epilepsy. In a single test, hundreds to thousands of genes are examined for DNA changes that may not only explain the etiology of the patient's condition but may also inform management and seizure control. Clinical genomic testing has been in clinical practice for less than a decade, and because of this short period of time, the appropriate clinical use and interpretation of genomic testing is still evolving. Compared to the previous era of single-gene testing in epilepsy, which yielded a diagnosis in <5% of cases, many clinical genomic studies of epilepsy have demonstrated a clinically significant diagnosis in 30% or more of patients tested. This review will examine key studies of the past decade and indicate the clinical scenarios in which genomic testing should be considered standard of care.

Utility of genetic testing in children with developmental and epileptic encephalopathy (DEE) at a tertiary hospital in South Africa: A prospective study

“…Diagnostic yields of different genomic tests have been reported in the literature. Clinicallyrelevant copy number variants (CNV), detected using CMA for childhood epilepsy, range from 5-13% (34).…”

“…The flow of patient selection and data collection is shown in Figure1.In 9 probands, the VUS(s) were deemed as "interesting candidates" as they fit based on phenotype, variant type and predicted functional consequence and inheritance pattern. Further testing/investigations are needed to reclassify these variants as likely pathogenic (Supplementary table 1-Patients 23,24,26,28,30,31,32,33,34).…”

A Review of the Prevalence, Etiology, Diagnosis, and Management of Pediatric Epilepsies in India

“…Genomics plays a vital role in characterizing the genetic basis of epilepsy and its syndromes. 43,44 Many Indian studies have pointed out the need for genetic testing in pediatric epilepsies to enable precision medicine. Structural brain malformations, birth injury, and inborn errors of metabolism can cause EIEE.…”

“…Copy-number variants (CNVs) contribute significantly to variations in the human genome. 43,44 Whole-genome sequencing is an initial diagnostic strategy that offers a potential time and cost-saving approach, with a turnaround of 14 days or less, and a more comprehensive single-step evaluation compared with the standard approach of multiple, sequential tests. 45 Because of the continued decline of sequencing costs, the use of whole genome analysis (WGA) is an efficient strategy for clinical diagnosis of EIEE and other genetic conditions.…”

Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients

“…This has led to a few limitations for current epilepsy genetics studies. For example, clinical genetic analysis is limited to variants near or within genes with a known association in human epilepsy disease with a focus on those in the coding regions, leading to the use of less than 1% of the genome sequencing data for clinical diagnosis (Thodeson and Park, 2019;Ellis et al, 2020). As a result, the expression and function of the noncoding sequence as a major component of the genome are being largely ignored and unexplored in prior epilepsy genetic studies.…”