1. Skills Workshop | Genetics Testing in Epilepsy Patients
Ingo Helbig, MD
Children’s Hospital of Philadelphia

2. Disclosure
I have nothing to disclose.

3. Learning Objectives Diagnostic work-up in suspected genetic epilepsies
Neonatal epileptic encephalopathy
Infantile/Epileptic Spasms
Patient with autism and epilepsy
Choice of the most appropriate testing modality

4. Resources – freely available
ILAE Genetic literacy series
Primer Part 1: The building blocks of epilepsy genetics
Primer Part 2: Paradigm shifts in epilepsy genetics
The Epilepsiome

6. Lab diagnostics versus epilepsy diagnostics
ClinGen
ILAE
ILAE classification
MONDO
GCI
HPO
Deep phenotyping
Genotype-phenotype correlations
SVI
Three-star variant
Lumping versus splitting
ACMG criteria
Historical classifications

7. Case 1 3 day-old boy Available information
Multifocal seizures, focal motor seizures of left or right arms and legs with head deviation
EEG with discontinuous pattern evolving to burst-suppression during sleep
No response to pyridoxine, various AEDs
Available information
Normal pregnancy, birth, delivery, 40+1, Apgars 6/8
No family history, no consanguinity

8. Diagnostic considerations
MRI
MRI findings
injury
malformation
no MRI findings
metabolic testing
positive
negative

9. Diagnostic considerations
MRI
MRI findings
injury
malformation
no MRI findings
metabolic testing
positive
negative

10. Diagnostic considerations
Neonatal epileptic encephalopathies:
EIEE, EOEE
MRI
MRI findings
injury
malformation
no MRI findings
metabolic testing
positive
negative

12. Diagnosis: KCNQ2 (Serino et al., 2013)
KCNQ2 encephalopathy
De novo NM_ (KCNQ2):c.740C>G (p.Ser247Trp)

13. Neonatal epileptic encephalopathy
Limited genetic architecture
50% of individuals have disease-causing variants
Genes: SCN2A, KCNQ2, CDKL5, STXBP1, SCN8A
First-line modality of choice
Epilepsy panel – all available panels cover the major genes
Rapid/non-rapid
Testing possible through clinical studies (e.g. ERGENT)

14. Case 2 6 month-old admitted for abnormal movements EEG
Unremarkable early development
Unremarkable pregnancy, delivery, neonatal period
EEG
Hypsarrythmia, bilateral flexor spasms
Diagnosis: West Syndrome

15. Diagnostic considerations EIEE vs. West Syndrome
MRI
MRI findings
injury
malformation
no MRI findings
metabolic testing
positive
negative
How well can we apply the neonatal work-up?

16. Diagnostic considerations EIEE vs. West Syndrome
MRI
MRI findings
injury
malformation
no MRI findings
metabolic testing
positive
negative
Metabolic work-up should be performed, but in parallel to genetics
How well can we apply the neonatal work-up?

17. Diagnosis: DNM1 (Dynamin 1)
DNM1 encephalopathy
De novo NM_ (DNM1):c.709C>T (p.Arg237Trp)
Pre-synaptic
Dynamin 1
Synaptic cleft
Post-synaptic

18. Infantile Spasms (without prior EIEE)
Wide genetic architecture
Large number of 1% genes, ~30% yield
New-onset spasms unlikely metabolic
No diagnostic yield in self-resolving spasms
First-line modality of choice
Epilepsy panel, then exome
Identify common genes first

19. Ohtahara syndrome (STXBP1, KCNQ2, SCN2A)
Neonatal onset, tonic seizures, burst suppression on EEG
Epilepsy of Infancy with Migrating Focal Seizures (KCNT1, SCN2A)
Refractory focal seizures, migrate from one region to another
0-3 months
West syndrome (CDKL5, STXBP1, ARX, DNM1)
Infantile spasms with hypsarrhythmia on EEG
Dravet syndrome (SCN1A)
Prolonged febrile/afebrile sz, focal (hemiclonic), regression
4 months –
2 years
Lennox-Gastaut syndrome (CDKL5, DNM1)
Refractory seizures (tonic), generalized slow-spike wave on EEG
Myoclonic-atonic epilepsy/Doose syndrome (SLC2A1, SLC6A1)
Febrile seizures, myoclonic-atonic seizures, regression
1-8 years
Landau-Kleffner syndrome (GRIN2A)
Acquired aphasia, previously normal devt, +/- seizures
Electrical status epilepticus during slow wave sleep
2-10 years

20. Case 3 15 male with autism and new-onset focal epilepsy Prior history
1x GTCS, 2x FIAS, EEG with left temporal spikes
Prior history
Unremarkable prenatal course, birth, postnatal period
Diagnosed with autism at age 2
Largely non-verbal, unremarkable MRI x2

22. Diagnosis 16p11.2 microdeletion
Common microdeletion in autism/intellectual disability
Diagnostic yield for microarray 15-20%
Deletions not identified through gene panel/exome
Deletion calling from panel/exome
In development, not ready for prime time yet

23. Diagnosis: Autism plus focal epilepsy
Question: is this an epileptic encephalopathy?
Not really
Does the presence of seizures change the work-up?
Patients with autism have a relatively high risk of seizures
EE is possible, but rare with onset at 15 years
Consider same work-up as with autism/intellectual disability

24. Learning Objectives Diagnostic work-up in suspected genetic epilepsies
Neonatal epileptic encephalopathy
Infantile/Epileptic Spasms
Patient with autism and epilepsy
Choice of the most appropriate testing modality