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Genetic Testing in Paediatric Epilepsy

Epilepsy can be caused by a variety of insults to the brain: birth related injuries, infection, trauma, structural abnormalities, tumours, and genetic factors. In certain cases, your Paediatric Neurologist or Epileptologist may refer you or your child for a genetic assessment.

In the Paediatric Comprehensive Epilepsy Clinic (CEC) for children living with Drug Resistant Epilepsy (DRE), we have a Medical Geneticist who works with our team and sees patients in our clinic that the Epileptologists have identified for genetic assessment.

Nature Reviews Neurology


How are epilepsy and genetics related?

Genetics 101: Chromosome vs Gene

  • We are all made up of cells and our genetic material, DNA, is inside the cell.
  • To fit inside the cell, DNA curls itself up into “chromosomes.”
  • “Genes” are portions of DNA with different functions.
  • We have about 22,000 genes. They come in pairs; one from the mother, one from the father.
  • Genes are like books that are stacked on shelves (chromosomes) inside our library (genome).
  • Genetic epilepsy can occur if there is a specific change (mutation or variant) on a chromosome or in a gene. 
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What are genetic changes (variants) leading to epilepsy?

  • CHROMOSOMAL CHANGES: Sometimes a gain (duplication) or loss (deletion) of a piece of a chromosome (eg. 15q13 deletion) involving many genes may cause epilepsy. These changes can be diagnosed with a microarray.
    • Chromosome changes don’t always cause disease; they may be inherited from a parent who does not have epilepsy. They may be considered disease causing if involving important genes and/or arising as a new change in the child (not inherited).
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  • SINGLE GENE CHANGES: There may be smaller changes inside a gene, much like a spelling mistake in a book.

    • Mutations (or pathogenic variants) that affect critical proteins controlling brain function and electrical stability may cause seizures.

    • There are hundreds of such genes, each known to cause a different type of monogenic epilepsy; e.g. SCN1A, STXBP1, SLC2A1, etc.

    • These can be diagnosed either by large gene panels or exome sequencing.

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  • GENETICALLY COMPLEX EPILEPSIES: Most cases of epilepsy are caused by a variety of mechanisms including multiple genetic and environmental factors. These can still run in families but cannot be diagnosed with chromosome or single gene testing

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Who needs testing?

  • Children who have severe early onset epilepsy (diagnosed in the first few years of their life)
  • Individuals diagnosed with both epilepsy and developmental delay or intellectual disability
  • Individuals not responding to anti-seizure medications (DRE)
  • Individuals suspected of having an underlying genetic syndrome due to physical features or issues in other organs
  • Individuals with distinctive seizure types
  • Family history of seizures

How do we diagnose genetic epilepsy?

Phase 1

  • An epilepsy diagnosis is made
  • Physical examination is completed
  • Development is assessed
  • Seizure type clarified (clinical/video EEG)
  • Age of Onset determined
  • Family history is completed

Phase 2

  • Video EEG study
  • MRI or CT to image the brain
  • Patient selection for genetics consult (Epilepstologist’s opinion based on criteria set by an expert panel at the provincial level)

Genetics Assessment:

  • History, family history, and physical examination by clinical geneticist
  • Depending on assessment, one or more of the below may be offered to the family:
    • Microarray and biochemical testing
    • Single gene testing (large panel)
    • Select individuals may get “exome sequencing”, parental samples may be needed
    • If all negative, families may be enrolled in research studies to find a genetic cause
    • Genetic counselling about testing and results
    • Reassessment in a couple of years
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Why do genetic testing?

  • Genetic testing provides a specific diagnosis in a portion of individuals tested (20-40% depending on age, seizure type, etc.)
  • A genetic diagnosis provides a reason for the issues and gives the family a sense of belonging and empowerment (“knowledge is power”)
  • A genetic diagnosis may provide a prognosis and may influence treatment choices. It is important to diagnose treatable causes of epilepsy as early as possible
  • A genetic diagnosis may help avoid further tests, multiple consults, repeat MRI’s and invasive monitoring
  • With a genetic diagnosis, families can get accurate counseling regarding recurrence risks and can make informed decisions in family planning

Final Thoughts…

  • Genetic testing in epilepsy is worth the effort in selected individuals. Not all epilepsy is genetic!
  • New technologies are rapidly influencing our understanding of the genetic basis of epilepsies
  • Next generation technologies are reducing costs of testing and providing new information almost on a daily basis.
  • The future – gene-specific treatments, enzyme replacement therapies, gene editing approaches, etc. holds the promise of providing personalized gene based therapies.
  • Genetic counselling is critical for families when a child is diagnosed with genetic epilepsy.

Resources for Families