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.

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.

    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).

    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.

    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

    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

      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