Genetic testing can provide information that directly impacts treatment options

Epilepsy is a group of phenotypically and genetically heterogeneous diseases that affect individuals of all ages and ethnicities. Genetic diagnosis can be difficult as a single gene can be associated with multiple epilepsy disorders (pleiotropy), and a single syndrome can have multiple genetic causes (genetic heterogeneity). Therefore, a multigene panel that includes many relevant genes is both time-saving and cost-effective.

Some of the genetic epilepsy syndromes, including several devastating childhood disorders, can be difficult to treat. Evaluation of the genetic basis of intractable epilepsy is one of the most frequent referral indications in neurogenetic clinics.¹ An accurate and early diagnosis in such cases is critical, as specific interventions may be indicated based on genetic findings.

Genetic testing for epilepsy is indicated to assist with patient management and is appropriate for individuals of any age with one or more of the following findings:

  • Clinical diagnosis is unclear
  • Clinical diagnosis is clear but not indicative of a treatable condition
  • Clinical features are consistent with a distinct electro-clinical syndrome
  • Treatable epilepsy is under consideration (e.g. early onset epilepsy, even if biochemical markers absent or not tested)
  • Early-onset or progressive myoclonic epilepsy
  • Epilepsy associated with additional syndromic features such as developmental delay, intellectual disability, multiple congenital anomalies, dysmorphic features

The seizure disorders covered by the genes in the Comprehensive Epilepsy Panel include generalized and focal genetic epilepsies, epileptic encephalopathies, progressive myoclonic epilepsies and epilepsies associated with X-linked mental retardation. Other genetic syndromes that include epileptic seizures as a major manifestation and inherited metabolic disorders that manifest as epilepsy are also included.

Case Study:

  • Female child with developmental delay and speech arrests (epileptic aphasia)
  • Onset of seizures at 3 years of age
  • Father had developmental delay and seizures as a child
  • Epilepsy gene panel testing reveals likely pathogenic variant in the GRIN2A gene
  • Parental testing reveals same mutation in father
  • Genetic diagnosis: Landau Kleffner syndrome (fits clinical presentation and EEG)
  • Prognosis: Symptoms expected to improve with age
  • Treatment: Based on Landau-Kleffner syndrome diagnosis, she received steroids and regained milestones
GENE DISORDER OMIM
DISORDERS THAT IMPACT MANAGEMENT*
ALDH7A1 Pyridoxine-dependent epilepsy and folinic acid-responsive seizures 266100
AMT Glycine encephalopathy 605899
FOLR1 Neurodegeneration due to cerebral folate transport deficiency 613068
GAMT Cerebral creatine deficiency syndrome 2 612736
GATM Cerebral creatine deficiency syndrome 3 612718
GLDC Glycine encephalopathy 605899
MOCS1 Molybdenum cofactor deficiency A 252150
PHGDH Phosphoglycerate dehydrogenase deficiency
(Serine deficiency syndrome)
601815
PNPO Pyridoxyl 5′ phosphate oxidase deficiency 610090
POLG Alpers syndrome and POLG related disorders 203700, 607459
PSAT1 Phosphoserine aminotransferase deficiency
(Serine deficiency syndrome)
610992
PSPH Phosphoserine phosphatase deficiency
(Serine deficiency syndrome)
614023
SCN1A Dravet syndrome and SCN1A related disorders 607208, 604403, 609634
SLC2A1 Idiopathic generalized epilepsy 12, infantile and childhood onset GLUT1 deficiency syndrome 614847, 606777, 612126
SLC6A8 Cerebral creatine deficiency syndrome 1 300352
SUOX Sulfite oxidase deficiency 272300
DISORDERS ASSOCIATED WITH A SEVERE PHENOTYPE
ARX Early onset epileptic encephalopathy/West syndrome 308350
CDKL5 Early infantile epileptic encephalopathy 2
(Atypical Rett/West syndrome)
300672
CHD2 Childhood-onset epileptic encephalopathy 615369
DNM1 Early infantile epileptic encephalopathy 31 616346
DOCK7 Early infantile epileptic encephalopathy 23 615859
GRIN2A Focal epilepsy with speech disorder with/without MR 245570
GRIN2B Early infantile epileptic encephalopathy 27 616139
HCN1 Early infantile epileptic encephalopathy 24 615871
KCNQ2 Early infantile epileptic encephalopathy 7 613720
MECP2 Rett syndrome, neonatal severe encephalopathy 312750, 300673
MEF2C Epilepsy with MR, stereotypic movement, and/or cerebral malformations (Atypical Rett syndrome) 613443
NECAP1 Early infantile epileptic encephalopathy 21 615833
PCDH19 Early infantile epileptic encephalopathy 9 300088
SCN1B Generalized epilepsy with febrile seizures plus, type 1 604233
SCN2A Early infantile epileptic encephalopathy 11, benign familial infantile seizures 3 613721, 607745
SCN8A Early infantile epileptic encephalopathy 13 614558
SPTAN1 Early infantile epileptic encephalopathy 5 613477
STXBP1 Early infantile epileptic encephalopathy 4 612164
SYNGAP1 Autosomal dominant mental retardation 5 612621
OTHER EPILEPSY SYNDROMES OF INFANCY
ATP1A2 Alternating hemiplegia of childhood 104290
ATP1A3 Alternating hemiplegia of childhood 2 614820
CHRNA7 Schizophrenia with neurophysiologic defect 118511
CNTNAP2 Cortical dysplasia-focal epilepsy syndrome / Pitt-Hopkins-like syndrome 1 610042
FOXG1 Rett syndrome (congenital variant) 613454
KCNJ10 EAST/SESAME syndrome 612780
KCNJ11 Neonatal seizures with Diabetes mellitus 606176
KCNQ3 Benign neonatal seizures type 2 121201
KCNT1 Nocturnal frontal lobe epilepsy 5, early infantile epileptic encephalopathy 14 615005, 614959
MBD5 Autosomal dominant mental retardation 1 156200
NRXN1 Pitt-Hopkins-like syndrome 2 614325
PLCB1 Early infantile epileptic encephalopathy 12 613722
PNKP Microcephaly, seizures, and developmental delay 613402
PRRT2 Familial infantile convulsion with paroxysmal choreoathetosis, benign familial infantile seizure 2 602066, 605751
SCN9A Generalized epilepsy with febrile seizures plus, type 7, familiar febrile seizures 3B, Dravet syndrome 613863, 607208
SLC9A6 X-linked syndromic mental retardation
(Christianson type)
300243
TBC1D24 Familial infantile myoclonic epilepsy, early infantile epileptic encephalopathy 16 605021, 615338
TCF4 Pitt-Hopkins syndrome 610954
TSC1 Tuberous sclerosis -1/infantile spasms 191100
TSC2 Tuberous sclerosis -2/infantile spasms 613254
UBE3A Angelman syndrome 105830
ZEB2 Mowat-Wilson syndrome 235730
PROGRESSIVE MYOCLONIC EPILEPSY
ASAH1 Spinal muscular atrophy with progressive myoclonus epilepsy 159950
CERS1 Progressive myoclonus epilepsy 8 616230
CSTB Progressive myoclonic epilepsy 1A
(Unverricht Lundborg)
254800
EPM2A Progressive myoclonic epilepsy 2A
(Lafora Body disease)
254780
GOSR2 Progressive myoclonus epilepsy 6 614018
KCNC1 Progressive myoclonus epilepsy 7 616187
KCTD7 Progressive myoclonus epilepsy 3 611726
LMNB2 Progressive myoclonus epilepsy 9 616540
NEU1 Progressive myoclonus epilepsy (sialidosis type I and II) 256550
NHLRC1 Progressive myoclonus epilepsy 2B
(Lafora Body disease)
254780
PRICKLE2 Progressive myoclonus epilepsy 5 613832
SCARB2 Progressive myoclonus epilepsy 4, with or without renal failure 254900

* These 16 genes are also available as a targeted panel (Management Impact Epilepsy Panel) in Canada

References

1. Kwan P, Schachter SC, & Brodie M J. NEJM. 2011; 365(10): 919-926. PMID: 21899452

 

◀ Benefits of Epilepsy Genetic Testing