Epilepsy in children can be due to several different causes, including structural, genetic, infectious, metabolic, immune, and unknown causes. In some children, despite extensive workup a cause is unknown.64
It is estimated that between 4% and 78% of patients with epilepsy of unknown etiology will be found to have a genetic variant that is likely to be significant.65 This can vary significantly with clinical indication and is highest in individuals with epileptic encephalopathies (17%), approximately 5% in patients with genetic generalized epilepsies, and lowest in patients with nonlesional focal epilepsies (2%).66
Over 80 genes have been identified as "epilepsy genes", with hundreds more known to cause other genetic disorders that can be accompanied by epilepsy or seizures.66
Utility of Genetic Testing for Epilepsy
Providing a unifying diagnosis as to the cause of an individual's symptoms
Identification of disorders with genotype-specific treatment
Allowing for targeted medical management of other symptoms associated with the condition
Providing additional prognostic information
Reducing the need for additional repeated studies such as neuroimaging
Allowing families to connect with a specific disease community and increase advocacy
Providing accurate recurrence risk information for patients and their families
Types of genetic testing
The genetic tests most commonly utilized in the evaluation of children with epilepsy include chromosomal microarray (CMA), epilepsy gene panels, and whole-exome sequencing (WES). Each test has its own specific benefits and limitations, and the diagnostic yield is variable. Currently, no specific guidelines exist to establish standards of practice for genetic testing in individuals with epilepsy and decisions regarding testing may be influenced by factors including clinical indication, turn-around time, insurance coverage, and cost. Although traditional practice often implements a stepwise approach consisting of chromosomal microarray, followed by epilepsy panel, followed by whole-exome sequencing,67 recent studies have suggested that this may not be the most-cost-effective approach.65
A general overview of each type of test is presented below:
Chromosomal microarray (CMA)- Chromosomal microarrays are designed to identify missing or extra pieces of genetic material, also known as copy number variants (CNVs). This is recommended as the first tier test for children with autism, developmental delay, and/or intellectual disability.68 The diagnostic yield for CMA in all patients with epilepsy is estimated to be approximately 8%, with various individual studies identifying ranges of 4-17%.65 This is likely to be higher in children with epilepsy and intellectual disability compared to children who have epilepsy without other comorbidities.69
Epilepsy gene panels- Gene panels utilize next-generation sequencing (NGS) technology to analyze multiple epilepsy-associated genes simultaneously. There are several commercial laboratories that currently offer this type of testing, and panels can vary dramatically in regards to number of genes included, ranging from approximately 100 to >500 genes, as well as cost and turn-around time. Certain labs may also offer smaller, more phenotype specific panels. Some panels may also include genes with disputed or limited gene-disease validity, meaning clear evidence confirming that variants in that gene cause epilepsy is lacking.70 The diagnostic yield of epilepsy gene panels is estimated to be approximately 23%65, though this may vary based on additional factors such as age of seizure onset, clinical indication, and family history.71
Whole-exome sequencing (WES)- WES utilizes NGS to sequence all of the exons, or protein coding regions, in an individual's DNA. Estimated diagnostic yield is approximately 32%,65 with higher diagnostic yields achieved when testing is performed using a trio-based analysis (child and both parents) versus proband only testing.72 Because this testing analyzes the entirety of an individual's exome, there is also the possibility for medically significant genetic variants to be identified in genes unrelated to epilepsy (secondary findings). It has therefore been recommended by the American College of Genetics and Genomics (ACMG) that patients undergoing genome-scale genetic testing, such as WES, provide written informed consent that is obtained by a qualified genetics health-care professional and that patients should be offered the option to opt-out of receiving secondary findings after receiving appropriate counseling regarding the implications of this.73
Points to consider when choosing a test
Individual tests can vary significantly in sensitivity, ability to identify variants of interest in disease genes, and diagnostic yield. For example, some gene panels can detect smaller, intragenic exon-level deletions and duplications whereas others cannot. Additionally, broad based tests such as WES may not provide 100% coverage for all genes of interest.
All genetic tests have the possibility of identifying "variants of uncertain significance," genetic changes for which the implications or clinical significance is unknown. In some cases, this uncertainty can be resolved by additional workup, such as testing of other family members. In other cases, this uncertainty may remain. More extensive testing, such as gene panels with more genes included, increases the likelihood of identifying these types of variants.
Testing may identify incidental findings, with unforeseen medical and psychosocial consequences.
Genetic testing that includes sequencing of multiple family members, such as trio-based WES, has the potential to identify unanticipated information such as misattributed paternity.74
A negative genetic test does not rule out the possibility that there is still an underlying genetic etiology for a child's epilepsy. This could be due to limitations to the testing technology, human error, or limitations to our current understanding, as our knowledge regarding epilepsy genetics is continually evolving.75 Reanalysis of exome sequencing data for patients in whom no diagnosis is initially found may therefore be warranted and may increase overall diagnostic yields.76
Because of these complexities, appropriate pre- and posttest counseling is imperative to ensure families understand the potential risks and benefits of genetic testing.77 Involvement of a genetic counselor or referral to a center with physicians experienced in epilepsy genetics should be considered whenever possible.
Links to major resources
Information about genetic counseling services as well as how to find a genetic counselor
Author: Holly Dubbs, MS, LCGC, Genetic Counselor, Children's Hospital of Philadelphia, Division of Neurology