Genetics & Epilepsy

Genes, inheritance and testing

Genetics can contribute to epilepsy in many different ways. Some epilepsies are caused mainly by a change in a single gene; others involve many genetic variants acting together with non-genetic factors. A genetic epilepsy may run in a family, but it may also appear for the first time in one person.

Genetic does not automatically mean inherited. A disease-causing variant can be passed down from a parent, arise de novo for the first time in an egg, sperm or early embryo, occur as mosaicism in only some cells, or contribute as one part of a more complex polygenic susceptibility.

Why genes can matter in epilepsy

Genes provide instructions that influence how brain cells develop, communicate and regulate electrical activity. Variants affecting ion channels, receptors, synaptic proteins, metabolism, brain development and many other processes can alter seizure susceptibility.

This does not mean every person with epilepsy has a single identifiable “epilepsy gene”. Epilepsy is an umbrella term covering many different disorders and syndromes. Some have a strong monogenic cause, some have a complex genetic contribution, some are structural or acquired, and some remain unexplained even after extensive investigation.

Single-gene, complex and polygenic epilepsy

In some epilepsy syndromes, a pathogenic variant in one gene can be the main cause. In many more common epilepsies, risk is influenced by many genetic variants, each contributing a small amount. Large genome-wide studies coordinated through the ILAE have identified multiple regions of DNA associated with epilepsy risk, particularly in genetic generalised epilepsies.

Polygenic risk is not the same as a single inherited disorder. It reflects the combined effect of many variants and does not usually allow a simple prediction that a particular relative will or will not develop epilepsy.

De novo variants

A de novo variant is a genetic change found in a person but not detected in either parent’s usual blood sample. These variants are important in several developmental and epileptic encephalopathies and help explain why a child can have a genetic epilepsy even when there is no family history.

“De novo” does not always mean recurrence risk for future pregnancies is absolutely zero. Rare parental germline mosaicism can exist even when a standard blood test is negative, so recurrence counselling is individual.

Mosaicism

Mosaicism means that a genetic variant is present in some cells but not all. It can occur in the person with epilepsy or, sometimes, in a parent. The proportion of cells carrying the variant can affect whether it is detectable in blood and may influence the clinical picture.

This is one reason why genetic interpretation is more complicated than simply asking whether a variant is “present” or “absent”.

Family history still matters

Clinicians may ask about epilepsy, febrile seizures, learning disability, autism, developmental differences, intellectual disability, unexplained infant deaths, movement disorders or other neurological conditions in relatives. A family history can suggest a genetic pattern even when no single causative variant is found.

Equally, having no family history does not rule out a genetic cause.

Who should be offered genetic testing?

Recommendations differ between healthcare systems and continue to evolve.

In England, NICE NG217 does not recommend testing every person with epilepsy. It advises discussing uncertainty with a neurologist or geneticist and referring to the NHS National Genomic Test Directory. NICE recommends considering whole-genome sequencing particularly when epilepsy is of unknown cause and starts under age 2, when a specific genetic epilepsy syndrome is suspected, or when epilepsy occurs with features such as learning disability, autism, congenital abnormalities or unexplained cognitive decline. For onset between ages 2 and 3, NICE says whole-genome sequencing can be considered if agreed by a specialist multidisciplinary team.

Other international guidance is broader. A 2023 evidence-based guideline from the US National Society of Genetic Counselors strongly recommended genetic testing for people with unexplained epilepsy regardless of age, using exome/genome sequencing and/or a multigene panel as first-tier testing, with appropriate genetic counselling. This difference is important: access and eligibility depend on country, healthcare system and clinical context.

What types of genetic test are used?

The best test depends on the clinical picture. Tests may include targeted testing for a specific suspected gene, multigene panels, chromosomal microarray, exome sequencing or whole-genome sequencing. Modern sequencing can examine many genes at once, while genome sequencing can also detect some changes outside protein-coding regions and certain structural variants.

No test detects every possible genetic cause. Technical limits, current scientific knowledge and the type of variant involved all affect what can be found.

What can a positive result change?

A confirmed genetic diagnosis can sometimes:

explain why epilepsy developed
refine or change the epilepsy syndrome diagnosis
help estimate prognosis in some conditions
influence treatment choices or medicines to avoid in selected genetic epilepsies
prompt screening for associated health problems
avoid repeated diagnostic investigations
guide testing or counselling for relatives
clarify recurrence risk for future children
identify eligibility for syndrome-specific research or clinical trials

The ILAE’s 2022 clinical genetic testing review emphasised that identifying a causative variant can improve individual care, while also recognising that the clinical impact varies greatly between diagnoses.

A result may not give a simple answer

Genetic testing can return several kinds of result. A pathogenic or likely pathogenic variant may support a diagnosis. A variant of uncertain significance (VUS) means there is not enough evidence to decide whether the change causes disease. A VUS should not be treated as proof of the cause of epilepsy.

A negative test also does not prove that epilepsy is non-genetic. The relevant gene may not yet be known, the variant may be difficult for the test to detect, or the epilepsy may result from many genetic and non-genetic factors rather than one identifiable variant.

Why results can change over time

Genetic interpretation is dynamic. New disease genes are discovered, variant databases grow and laboratory classification can change as evidence accumulates. A result that was uncertain or negative years ago may sometimes be worth re-analysis, especially when the clinical picture strongly suggests a genetic epilepsy.

Whether re-analysis is available, when it should be done and who arranges it varies between services.

Testing can affect more than one person

A genetic result may have implications for parents, siblings, children and wider relatives. It can raise questions about inheritance, reproductive choices, predictive testing and whether other family members should be offered testing.

That is why NICE recommends informed consent and appropriate genetic counselling before testing. The possible benefits, limitations, uncertain results and implications for relatives should be discussed rather than treating genetic testing like an ordinary blood test.

Genetic does not mean inevitable

Some disease-causing variants have high penetrance, meaning many people who carry them develop symptoms. Others have reduced penetrance, so some carriers may remain unaffected. Expression can also vary: relatives with the same variant may have different seizure types, severity, age of onset or associated features.

So even when a gene is known, genetics does not always predict an individual person’s future with certainty.

Genetics is not the same as blame

A genetic diagnosis is not something a parent caused by an action, diet, stress or parenting. De novo variants arise naturally, and inherited variants are passed through biology rather than choice. Genetic counselling can help families understand this and work through feelings such as guilt, fear or uncertainty that may follow a diagnosis.

Sources and guidance

NICE NG217 — Diagnosis, assessment and genetic testing

NICE NG217 — Rationale and impact: genetic testing

NICE Evidence Review C — Effectiveness of genetic testing

International League Against Epilepsy — Epilepsy and Genetics

ILAE Genetics Commission — Current practice in diagnostic genetic testing of the epilepsies

National Society of Genetic Counselors — Evidence-based genetic testing and counselling guideline

ILAE — Large genome-wide study of epilepsy genetics

Medical note: Genetic testing should be selected and interpreted in the context of the person’s seizure history, examination, EEG, imaging, development and family history. A genetic result should not be used in isolation to diagnose or change treatment.

Evidence checked: September 2026.