Genetic Testing Overview
- Epilepsy in children can be due to different causes, including changes in the brain’s structure, genetic changes, infections, metabolic disorders, and disorders where the body’s immune system reacts to itself (autoimmune disorders). In some children a cause may not be determined, despite extensive testing.
- Genetic changes refer to changes in a person’s genes, the information stored in a person’s body that tells different parts of the body how to grow and function. These changes can be inherited from a person’s parents or have newly occurred while the person was developing very early in life.
- In many individuals with epilepsy without a clear structural cause genetic testing may reveal a significant change. The utility of genetic testing can vary significantly with clinical indication and is highest in individuals with in individuals with conditions where epilepsy is associated with developmental delays, conditions where epilepsy is associated with developmental delays. While new genetic causes of epilepsy continue to be identified, currently, genetic causes of epilepsy have also been identified in generalized epilepsies or focal epilepsies.
- Over 200 genes have been identified as "epilepsy genes", with hundreds more known to cause other genetic disorders that can be accompanied by epilepsy or seizures.
Why Genetic Testing is Helpful for Epilepsy
- Provides a unifying diagnosis as to the cause of an individual's symptoms.
- Identifies disorders with specific treatments.
- Allows for targeted medical management of other symptoms associated with the condition.
- Provides additional prognostic information.
- Reduces the need for additional repeated studies such as neuroimaging.
- Allows families to connect with a specific disease community for support and to coordinate advocacy and research efforts.
- Provides accurate recurrence risk information for affected individuals and their families.
Types of Genetic Testing
The genetic tests most 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 utility of different tests may vary for a given individual. Decisions regarding testing need to consider the clinical indication including associated symptoms, turn-around time, insurance coverage, and cost. Because genetic testing is complicated and has implications regarding future eligibility for life insurance, disability insurance, reproductive decisions, and other medical decisions, involving a genetic counselor and/or medical geneticist is ideal when possible.
A general overview of each type of test is presented below:
Karyotype - A karyotype is a test that visualizes the size, shape, and number of chromosomes. In addition to identifying whether an individual has an extra chromosome or missing chromosome (aneuploidy), careful analysis of a karyotype can also reveal changes in the structure of chromosomes such as large deletions, duplications, translocations, or inversions of the genetic material.
Chromosomal microarray (CMA) - Chromosomal microarrays are designed to identify missing or extra pieces of genetic material, also known as copy number variants (CNVs). This test may be abnormal in approximately 10% of individuals with epilepsy and is more likely to be abnormal in children with epilepsy and other conditions such as autism, developmental delay, and/or intellectual disability.
Epilepsy gene panels - Gene panels utilize next-generation sequencing (NGS) technology to analyze multiple genes known to be associated with epilepsy simultaneously. There are several commercial laboratories that currently offer this type of testing, and panels can vary dramatically regarding the number of genes included, ranging from approximately 100 to >500 genes, as well as cost and turn-around time. Some panels may also include genes where the association with epilepsy is disputed. The diagnostic yield of epilepsy gene panels is approximately 20%, though this may vary based on additional factors such as age of seizure onset, clinical indication, and family history.
Whole-exome sequencing (WES) - WES utilizes NGS to sequence all the exons, or protein coding regions, in an individual's DNA. WES is explanatory in approximately 30% of patients with epilepsy. The likelihood the test will be explanatory for a person’s epilepsy is higher when the child as well as both biological parents are tested (trio-based analysis). 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 Medical 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.
Whole-genome sequencing (WGS) - WGS utilizes NGS to sequence all the exons as well as all the introns, or non-protein coding regions of an individual’s DNA. Currently WGS is primarily available on a research basis and is not yet use in routine clinical practice.
Points to Consider When Choosing a Genetic Test
- Individual tests can vary significantly in their ability to identify variants of interest in disease genes. For example, some gene panels can detect small deletions and duplications whereas others cannot. Additionally, broad 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 or WES, increases the likelihood of identifying these types of variants.
- Testing may identify incidental or secondary findings, such as changes in genes associated with heart disease or an increased risk for cancer, 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.
- 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 rapidly evolving. Reanalysis of exome sequencing data for patients in whom no diagnosis is initially found may therefore be warranted and may increase overall diagnostic yields.
- Because of these complexities, appropriate pre- and post-test counseling is imperative to ensure families understand the potential risks and benefits of genetic testing. Involvement of a genetic counselor or referral to a center with physicians experienced in epilepsy genetics should be considered whenever possible.
For more details, check out these helpful resources:
- AAP Policy Statement: Ethical and Policy Issues in Genetic Testing and Screening of Children
- AAP Council on Genetics
- New Guidelines on Genetic Testing and Screening in Children
- Epilepsy Foundation: Genetic Testing and Epilepsy
- National Coordinating Center for the Regional Genetics Networks
- National Society of Genetic Counselors: Information about Genetic Counseling Services
American Academy of Pediatrics