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

Disclosure I have nothing to disclose.

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

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 www.epilepsygenetics.net

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

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

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

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

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

Diagnosis: KCNQ2 (Serino et al., 2013) KCNQ2 encephalopathy De novo NM_172107.3(KCNQ2):c.740C>G (p.Ser247Trp)

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)

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

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?

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?

Diagnosis: DNM1 (Dynamin 1) DNM1 encephalopathy De novo NM_004408.3(DNM1):c.709C>T (p.Arg237Trp) Pre-synaptic Dynamin 1 Synaptic cleft Post-synaptic

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

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

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

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

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

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