Genetic Testing in Adults with Epilepsy

The role of genetic testing in clinical neurology has increased dramatically in recent years. Epilepsy is no exception, with many causative genes now identified,¹ a growing list of effects on treatment resulting from genetic diagnoses,² and emerging gene-specific treatments in clinical trials or preclinical development.³ The fact that many genetic epilepsies are severe, early-onset epilepsies (eg, epileptic encephalopathies) may give the false impression that genetic epilepsies are limited to pediatric neurology clinics. In reality, many adults have epilepsies with identifiable genetic causes. Neurologists should be aware of common indications for genetic testing and should be able to order the testing themselves or refer appropriate individuals to a genetics clinic. The goal of this review is to offer practical, evidence-based guidance about genetic testing for clinicians caring for adults with epilepsy.

Indications: Whom to Test?

Recent expert guidance on genetic testing for epilepsy comes from the International League Against Epilepsy (ILAE) Genetic Commission and Task Force on Clinical Genetic Testing in the Epilepsies.⁴ Here we interpret that guidance as it pertains to adults. Genetic testing should be considered in each of the following circumstances described in this section (Table 1).

Epilepsy Plus

This category includes epilepsy with comorbid intellectual disability, autism, dysmorphic features, or multiple congenital anomalies, all of which are well-established indications for genetic testing with high diagnostic yields.⁵ Intellectual disability and epilepsy are frequently comorbid,⁶ making this a particularly common indication for genetic testing. In our practice, we also include epilepsy plus other neurologic signs or symptoms that are atypical for epilepsy, such as ataxia or progressive cognitive decline.

Epileptic Encephalopathies

This term refers to cases where epileptic activity itself contributes to severe cognitive and behavioral impairments, with the implication that ameliorating the epileptiform activity may improve the developmental outcome.⁷ Not all cases of comorbid epilepsy and intellectual disability are epileptic encephalopathies, although many epileptic encephalopathies do involve an independent developmental abnormality, broadly termed developmental and epileptic encephalopathies. Examples of epileptic encephalopathies that may transition to adulthood include Lennox-Gastaut syndrome, Dravet syndrome, and epilepsy with continuous spikes and waves during sleep. These diagnoses can be challenging for adult neurologists because some of the classic symptoms in children may recede in adulthood (eg, slow spike and wave for Lennox-Gastaut syndrome, fever-sensitive myoclonic seizures for Dravet syndrome), and other features may emerge (eg, crouched gait in Dravet syndrome).^8–11 Adult neurologists should ask about a history of infantile spasms, febrile seizures and status epilepticus in early childhood, and overnight EEG recordings which can provide clues to these diagnoses.

Familial Epilepsies

A family history of epilepsy should raise suspicion for a genetic cause. The ILAE guidelines do not define a threshold of how strong a family history should be to indicate genetic testing. In our practice, we include individuals with epilepsy who have 1 or more first-degree relatives with epilepsy (a parent, sibling, or child); 2 or more second-degree relatives with epilepsy (a grandparent, aunt or uncle, or niece or nephew); or 3 or more total relatives with epilepsy. A detailed family history is therefore an important aspect of any epilepsy evaluation. Most familial epilepsies are dominantly inherited, although recessive and X-linked forms also exist. Several well-defined familial epilepsy syndromes are associated with particular genetic causes, including autosomal dominant sleep-related hypermotor epilepsy, autosomal dominant epilepsy with auditory features, familial focal epilepsy with variable foci, genetic epilepsy with febrile seizures plus, and familial adult myoclonic epilepsy.⁴

Drug-Resistant Epilepsy of Unknown Cause

In the absence of the listed criteria, genetic testing should be considered in individuals with drug-resistant epilepsy and no known acquired etiology, because identifying a genetic cause might lead to targeted treatment options.¹²

Genetic epilepsies can be generalized or focal. An individual’s epilepsy type therefore should not be a factor in considering genetic testing. Although the idiopathic generalized epilepsies are particularly heritable, the yield of genetic testing is paradoxically higher in the focal epilepsies, probably because idiopathic generalized epilepsies are largely polygenic (caused by the aggregate effect of many genetic variants), whereas current genetic testing is limited to monogenic causes.

The individual’s age should not influence the decision to test. Adults whose epilepsy began in childhood and who would likely be offered genetic testing if they were children today and met one of the listed criteria should be considered testing candidates as adults. Earlier age at onset, particularly onset during infancy, is associated with a higher likelihood of a genetic diagnosis.^13–15 However, genetic diagnoses also occur in people with epilepsy onset during childhood, adolescence, or adulthood.¹⁵ Therefore, although early-onset epilepsy should raise the consideration of genetic testing, older ages at onset are not contraindications to testing in individuals meeting one of the above criteria.

The criteria presented here are the most common indications for genetic testing, but the list is not exhaustive. Some genetic epilepsies have recognizable phenotypes of which clinicians should be aware. Examples include the progressive myoclonic epilepsies, characterized by myoclonus, ataxia, and cognitive decline; bilateral periventricular nodular heterotopia, particularly the classic contiguous, symmetric pattern in women, caused by variations in FLNA; neuronal migration defects, such as lissencephaly and subcortical band heterotopia; familial cerebral cavernous malformations, attributable to 3 genes; and tuberous sclerosis complex, caused by variations in TSC1 or TSC2.

Approach to Testing: What Tests to Send?

Exome or genome sequencing are the recommended first-line tests for people with epilepsy.⁴ Historically, many clinicians have sent gene panels, which sequence only a selected list of genes. The disadvantages of this approach are that gene lists vary among laboratories and the results cannot be updated as new genes are discovered over time. With more than 900 known epilepsy genes and more being discovered,¹ a broad testing approach is best. The ILAE guidelines recommend that gene panels be performed only when exome or genome sequencing is not available.⁴ Gene panels may have a role when exome or genome sequencing is not covered by insurance and cost is prohibitive. Copy number variants (microdeletions or duplications) can be detected reliably by exome and genome sequencing, so additional testing for these genetic changes (eg, chromosomal microarray) usually is unnecessary.

Exome sequencing refers to high-throughput sequencing of the protein-coding portion of the genome. Although this represents less than 2% of the entire human genome, most known genetic causes of human disease are within the exome. Advances in technology and falling costs have made exome sequencing widely available in many health care settings. Genome sequencing covers the entire human genome, including noncoding regions. Genome sequencing has a higher diagnostic yield than exome sequencing,⁵ although challenges regarding interpretation of noncoding variants, data storage, and cost limit its widespread clinical use.

A genetic variant is any change in DNA sequencing compared to standard reference human genome sequencing. Criteria from the American College of Medical Genetics are used to classify variants into 1 of 5 categories: pathogenic, likely pathogenic, uncertain significance, likely benign, or benign.¹⁶ In clinical practice, variants classified as pathogenic or likely pathogenic are considered diagnostic, assuming the gene’s clinical phenotype and mode of inheritance fit the clinical picture. Variants of uncertain significance (VUS) are common findings and can be challenging for individuals and health care providers alike. VUS should not be presumed causative without additional evidence, nor should they be used to guide management. When performing exome or genome sequencing, simultaneously testing the individual and both parents (trio approach) improves variant interpretation and reduces the number of VUS.

Although exome and genome sequencing are broad tests, there are some genetic causes of epilepsy they may fail to detect. Repeat expansions may be missed by exome sequencing, and detection improves with genome sequencing.¹⁷ In epilepsy, repeat expansions are associated with fragile X syndrome, Unverricht-Lundborg progressive myoclonic epilepsy, DRPLA (dentatorubral-pallidoluysian atrophy), and familial adult myoclonic epilepsy. Noncoding variants, which are variants outside the protein-coding exon sequences, are not detected by exome sequencing; although they are detected by genome sequencing, interpretation of noncoding variants remains a challenge. Ring chromosomes are rare genetic causes of epilepsy that may only be detected by conventional karyotype. Methylation analysis of the UBE3A gene is necessary when Angelman syndrome is suspected.

Genetic testing is restricted to monogenic causes (epilepsies caused by a single variant in a single gene); however, some of the genetic basis of epilepsy, particularly familial epilepsy, is likely polygenic (ie, caused by the aggregate effects of many risk alleles spread across the genome).¹⁸ Testing individuals for polygenic risk of epilepsy is not clinically available.

Diagnostic Yield of Genetic Testing In Adults

The largest study to date of the diagnostic yield of genetic testing in adults with epilepsy included more than 2,000 participants who had commercial gene panels covering 89 to 189 genes.¹⁵ The overall diagnostic rate was 11%. Adults with seizure onset in the first year of life had the highest diagnostic rate (30%). Regarding the specific indications of testing discussed previously, the diagnostic rate for those with intellectual disability was 16%; for those with a reported family history of epilepsy, 9%; and for those with drug-resistant epilepsy, 14%.

Other studies of genetic testing in adults with epilepsy have reported diagnostic yields ranging from 11% to 47%, with heterogeneity of populations and testing strategies (Table 2). These findings in adults are broadly in line with a much larger literature on genetic testing in children with epilepsy, or in unselected individuals who were mostly children. Two recent meta-analyses of this literature found overall diagnostic yields of 17% and 24%.^5,19 Higher diagnostic yields in those with early-onset epilepsies and those with intellectual disability have been consistent findings.

Clinical Effects

A genetic diagnosis has many potential effects on an individual’s health care. In the largest study of genetic testing in adults with epilepsy, 55% of all genetic diagnoses were considered clinically actionable,¹³ defined as indications or contraindications for certain antiseizure medications (ASM), inherited metabolic disorders with available treatments, or potential indications or contraindications for surgery. A genetic diagnosis may affect treatment selection of standard ASM (eg, avoiding sodium channel–blocking ASM in epilepsies caused by variations in SCN1A), or provide opportunities for evidence-based use of uncommon ASM, such as fenfluramine and stiripentol for Dravet syndrome.² In some cases, medications that are not traditional ASM but are approved for other indications may be repurposed to counteract the molecular mechanism of a genetic epilepsy, such as memantine for GRIN2A gain of function, and quinidine for KCNT1 gain of function.²

New genetic therapies, such as vector-delivered gene modification and antisense oligonucleotides, are in preclinical development for several of the genetic epilepsies, and some have entered human clinical trials.³ This is an exciting frontier across neurology and genetics and is sure to alter the landscape of epilepsy treatment in the near future. More widespread genetic testing in clinical practice will help identify individuals who are eligible for these trials and targeted treatments in the future.

A genetic diagnosis has several other potential implications for the individual beyond medical treatment. It can provide an explanation for why the person has epilepsy; help avoid unnecessary testing and exposure to potentially harmful interventions; assist in prognostication and planning for future health care needs; allow screening for comorbidities, such as other organ system involvement; identify and provide genetic counseling for at-risk relatives; and influence family planning. For individuals with a genetic condition who are seeking to have children, preimplantation genetic diagnosis is an available reproductive technology to prevent the transmission of known pathogenic variants to future children—another potential benefit of making a genetic diagnosis.

Conclusions

Genetics and genetic testing have an important role in the care of people with epilepsy across the lifespan. Neurologists and other health care providers should be familiar with common indications for genetic testing in adults with epilepsy. Exome or genome sequencing is the recommended first-line test. Diagnostic yields are substantial as are the potential clinical ramifications of a genetic diagnosis.