Epilepsy

Genetic Testing for Epilepsy

A Guide for Clinicians

KNOWING WHAT TO LOOK FOR

KNOWING WHERE TO LOOK

AND KNOWING WHAT IT MEANS

Figure 1.

Introduction
Epilepsy is a common neurological disorder that affects at least 0.8% of the population. It is
defined by the occurrence of at least two unprovoked seizures occurring more than 24 hours
apart. Seizures are the manifestation of abnormal hypersynchronous discharges of cortical
neurons lasting for several seconds, minutes, or longer. The clinical presentation of seizures
depends upon both the location of the epileptic discharges in the cortex and the extent and
pattern of propagation of the electrical discharges in the brain.
In many cases, seizures result in convulsions and loss of consciousness. Seizures may also
manifest in other ways that affect personality, mood, memory, sensation, and/or movement. Blank
stares, lip smacking, intermittent eye movements, and jerking movements of the extremities are
all examples of possible manifestations of seizures. In some cases these may not be recognized
as a seizure by patients, their family members, or even health care professionals. Seizures can
be classified into various categories (Figure 1).
PLEASE REDRAW to make it look similarly to the one in the guide.

FIGURE 1: Types of seizures.

Generalized Tonic-Clonic 12-24%

Complex Partial 8-31%

Absence 5-22%
Simple Partial 2-12%

Infantile Spasms 1-9%

Myoclonic 1-11%

Other Partial 7-29%

Other Generalized <1-3%

Unclassified/Mixed 4-43%

Reference: Cowan, LD. The epidemiology of the epilepsies in children. Ment Retard Develop
Disab (2002) 8:171-181.

Etiology
Epilepsy may be an isolated neurological symptom, or it may occur as part of a more complex
syndrome. There are many different causes of epilepsy, including genetic disorders, metabolic
diseases, and structural brain abnormalities. However, in some cases, the cause of epilepsy
is not known. The International League against Epilepsy (ILAE) has described the underlying
causes of epilepsy as the following.3
Genetic: The concept of genetic epilepsy is that the epilepsy is, as best as understood, the
direct result of a known or presumed genetic defect(s) in which seizures are the core symptom

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS

of the disorder.3 The genetic contribution must be evident by extensive and replicable molecular
studies or familial studies, e.g., SCN1A gene has been demonstrated to be associated with GEFS+.9
Structural/metabolic: If there is a specific structural or metabolic disorder that has been proven
in various studies to be associated with increased risk of epilepsy, the cause of epilepsy can
be defined as structural or metabolic. The cause for such a disorder can be acquired (e.g.,
trauma, stroke, infection), genetic (e.g., malformations of cortical development) or both (e.g.,
West syndrome).
Unknown cause: This means that the underlying cause is yet unknown. Epilepsy might be
presenting because of either some genetic defect or as a result of disorder that is not yet
recognized.

Diagnosis of Epilepsy
Clinical and family history
The detailed clinical history may help confirm that the seizure events are in fact epileptic seizures,
rather than non-epileptic events such as fainting, breath-holding, transient ischemic attacks,
strokes, arrhythmias, or hypoglycemia, all of which can manifest similarly to epileptic seizures.
A detailed clinical history also may help clarify potential triggers and diurnal patterns related to
seizure events. The medical history will help to determine if the seizures are isolated or part of a
larger syndrome. In addition to clinical history for the affected individual, a family medical history
should be obtained, including any history of seizures and other neurodevelopmental disorders
in any relatives. This information may help clarify the type of epilepsy in a family, including the
mode of inheritance and the prognosis.

Electroencephalogram (EEG)
Children with a known or suspected diagnosis of epilepsy based on clinical and family history
should undergo an EEG to help confirm the seizure type, and to evaluate recurrence risk for
future seizures. An EEG may also provide important information for making treatment decisions
(Figure 2).

Physical examination
In some cases, an individual with epilepsy may have other related neurological abnormalities,
medical problems, or dysmorphic features that can be identified by physical examination. For
example, many genetic syndromes involving epilepsy also cause developmental delay, hypotonia,
birth defects, ataxia, dystonia, microcephaly or macrocephaly, dysmorphic facial features, or
other features that can be noted in a physical examination.

Genetic testing
The information obtained from clinical and family histories, physical examination, and EEG can
help a clinician determine whether genetic testing should be offered to a patient with epilepsy
and which specific genetic test(s) may be appropriate.2
2

Genetics of Epilepsy
The last decade has witnessed the discovery
of many genes involved in epilepsy. Most
of these genes are expressed in the brain
and encode subunits of ion channels that
play vital roles in stabilizing or propagating
neuronal activity. Disruption of these genes
in general induces neuronal hyperexcitability,
thus causing seizures. As described above,
there are many forms of epilepsies. A single
gene may be associated with different
forms of epilepsy, but one type of epilepsy
may also result from defects in any one
of a variety of genes.5 Inherited channels
caused by mutations in ion channel or
neuroreceptor genes (e.g., SCN1A-related
disorders and KCNQ2, KCNQ3 mutations
in benign familial neonatal seizures) can
present with seizures.9 Rarely epilepsy
syndromes can be the result of severe
mutations in single genes whereas more
commonly epilepsy is likely to be caused
by the combined effect of variants in a
number of genes that cannot be currently
defined. Examples of monogenic causes of
epilepsy are pyridoxine-dependent epilepsy
and neuronal ceroid lipofuscinoses (NCL).
In some cases, copy number variations
associated with neuropsychiatric disorders
can be involved in epilepsy too. It is well
known that the 1p36 microdeletion, WolfHirshhorn, Miller-Dieker, Pallister-Killian, and
Angelman syndromes include epilepsy as
a major feature, but these disorders also
involve various other clinical features as
well.2 Table 1 shows the common genetic
disorders that have been associated
with epilepsy. Some rare mitochondrial
disorders, such as MERRF and MELAS
can also present with epilepsy as one of
the symptoms.1

FIGURE 2: Typical EEG abnormalities for

different types of seizures.

Normal EEG (9yr-old child)

Modified hypsarrhythmia during sleep in patient

with infantile spasms (8mo-old infant)

Generalized spike wave in

patient with absence epilepsy (3yr-old child)

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS

Table 1: Genetic disorders associated with Epilepsy

Syndrome

Clinical Presentation

Inheritance

Genes

Adenylosuccinate
lyase deficiency

Psychomotor delay, intellectual disability,

intractable seizures autism

AR

ADSLI,C,A

Angelman/Angelmanlike syndromes

Developmental delay, onset

at >6 months of age, ataxia,
tremulousness, happy appearance, microcephaly, seizures

AD

CNTNAP2I,C,A
SLC9A6I,C,A
NRXN1I,C,A
TCF4I,C,A
UBE3AI,C,A

Autosomal dominant
nocturnal frontal
lobe epilepsy

Seizures arising from sleep,

prominent motor manifestations

AD

CHRNA2C,A
CHRNA4C,A
CHRNB2C,A

Autosomal dominant
partial epilepsy with
auditory features

Ictal auditory symptoms and

receptive aphasia, secondary
generalization, benign course

AD

LGI1C,A

Baltic myoclonus
(Unverricht-Lundbord
disease)

Individuals in late childhood or

adolescence with photosensitive
myoclonus, seizures, ataxia

AR

CSTBC,A,P

Benign familial
neonatal-infantile
seizures (BFNIS)

Seizures from 2 days of age to

6 months, normal development

AD

SCN2A,I,C

Benign familial neonatal

seizures (BFNS)

Neonatal seizures at approximately 3

days of age, resolution at <1 month of
age, generalized or focal tonic-clonic
seizures, normal development

AD

KCNQ2I, KCNQ3I

Creatine deficiency
syndromes

Developmental delay, seizures,

positive magnetic resonance
spectroscopy, autism

Various

GAMTI,C, GATMC
SLC6A8C

Early-onset epileptic
encephalopathy and/
or infantile spasms

Early onset, multiform and

intractable seizures, cognitive,
behavioral, and neurological

Various

ALDH7A1I, ARXI
ATP6AP2I
CDKL5I,C
PCDH19I,C
POLGI,C,A
PNPOI, SCN1AI,C
SLC2A1I,C,A
SLC25A22I
SPTAN1I
STXBP1I

Epilepsy with variable

learning and behavioral
disorders

Variable clinical presentations with combinations of epilepsy, learning difficulties,

macrocephaly, and aggressive behavior

XL

SYN1C,A

Generalized epilepsy
with febrile seizures
plus (GEFS+)

Onset of febrile seizures at <1 year of

age, persistence beyond age 6 years,
evolution to mixed seizure types

AD

GABRG2I,C
SCN1AI,C
SCN1BI,C
SCN2AI,C

Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhoodonset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel
4

Syndrome

Clinical Presentation

Inheritance

Genes

Glucose transporter
Type I deficiency
syndrome

Early-onset refractory seizures,

movement disorders, ataxia, progressive encephalopathy, acquired
microcephaly, and spasticity

AD

SLC2A1I,C,A

Juvenile Myoclonic
Epilepsy (JME)

Typically seizures begin between

late childhood and early adulthood,
characterized by quick jerks of the arms,
shoulder, or occasionally the legs

AD

CACNB4C,A
EFHC1C,A
GABRA1C,A

Lafora disease

Progressive myoclonus, myoclonic

epilepsy, absences, and dementia

AR

EPM2AC,A,P
EPM2BC,A,P

Microcephaly with
early-onset intractable
seizures and developmental delay (MCSZ)

Infantile-onset seizures accompanied

by microcephaly developmental
delay and various behavioral
problems (typically hyperactivity)

AR

PNKPI

Mowat-Wilson
syndrome

Distinctive facial features, Hirschsprung

Disease, intellectual disabilities, genital
abnormalities, congenital heart disease,
agenesis of the corpus callosum, seizures,
eye defects and severe speech impairment.

Various

ZEB2I,C

Neuronal Ceroid
Lipofuscinoses (NCL)

Intellectual and motor deterioration,

seizures, visual loss, and early mortality

AR

CLN3I,C,A,P
CLN5I,C,A,P
CLN6I,C,A,P
CLN8I,C,A,P
CTSDI,C,A,P
MFSD8I,C,A,P
PPT1I,C,A,P
TPPI,C,A,P

Ohtahara syndrome

Suppression burst on electroencephalogram, tonic seizures

Various

STXBP1I, ARXI

Progressive Myoclonic
Epilepsy (PME)

Myoclonic seizures, cognitive

impairment, ataxia, and dementia

AR

PRICKLE1C,A,P

Pyridoxine dependent seizures

Vitamin B6-responsive seizures

AR

ALDH7A1I

Rett/Atypical Rett
syndrome

Rett Syndrome: Regression then

stagnation, onset at <18 months of
age, loss of purposeful hand movements, acquired microcephaly
Atypical Rett Syndrome:
Early-onset seizure variant of Rett
syndrome, Infantile spasms

Various

CDKL5I,C
FOXG1I,C
MECP2I,C

West Syndrome

Infantile spasms, hypsarrhythmia, encephalopathy

Various

TSC1I, TSC2I
CDKL5I,C, ARXI
STXBP1

There are 4 subpanels and a comprehensive panel available to order. ATP1A2 and SRPX2 are not part of any subpanel,
but are included in the comprehensive panel along with all the other genes listed in this table.
Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhoodonset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel
GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS

Clinical Utility of Genetic Testing

Genetic testing for epilepsies is often complex because mutations in so many different genes
can cause seizures. Nevertheless, genetic testing can be useful in certain clinical scenarios
when it can help in clarifying the prognosis, assist in treatment and management of the patient,
and predict the risk of a disease in family members. Genetic testing is termed diagnostic if
the patient is symptomatic and predictive if the patient is asymptomatic, but at risk for having
a disorder in the future.1

TABLE 2: Clinical utility of genetic testing

1. Diagnostic testing in an individual with epilepsy

Confirm a clinical diagnosis of a specific genetic syndrome or type of epilepsy

Distinguish between syndromic and non-syndromic forms of epilepsy
Establish the genetic cause of idiopathic epilepsy
Provide information about prognosis
2. Assistance with selection of optimal treatment options
3. Predictive testing for asymptomatic family members of a proband with a
known disease-causing mutation associated with a genetic form of epilepsy
Enable clinical monitoring, follow-up, and optimal treatment when symptoms
develop in an individual with a positive result

Reduce anxiety and forego clinical monitoring if result is negative

4. Prenatal diagnosis in at-risk pregnancies for known, pathogenic mutations
5. Genetic counseling, recurrence risk determination, and family planning

Utility of genetic testing in treatment:

The treatment of epilepsy depends upon the type of seizure, age of the patient, and other factors.
Knowledge of the genetic etiology of epilepsy may guide selection of the most appropriate
treatment options in some cases. A number of antiepileptic medications are used in the treatment
of epilepsy. The specific type and etiology of seizures may influence the selection of antiepileptic

medication for each patient. For example, certain medications may be more effective for infantile
spasms and are therefore first choices for patients with spasms. Likewise, certain medications
may be contraindicated for patients with a specific electroclinical or genetic diagnosis (Table
3). Dietary modifications including the ketogenic diet are useful in certain conditions1 such as
for patients with glucose transporter type 1 deficiency syndrome (SLC2A1 gene).

TABLE 3: Genetic test results applied to therapeutic decision-making

Disorder

Genes

Treatment Implications

Alpers-Huttenlocher and other

POLG-related disorders

POLG

Avoid valproic acid, which can

induce or accelerate liver disease

Creatine deficiency syndromes

SLC6A8,
GAMT, GATM

Oral creatine (GAMT, AGAT)

GEFS+, and other SCN1Arelated disorders

SCN1A

Valproate, clobazam, stiripentol, levetiracetam, topiramate. Avoid phenytoin,

carbamazepine, and lamotrigine.

Glucose transporter type

1 deficiency syndrome

SLC2A1

Seizures typically respond

to a ketogenic diet

Pyridoxal 5-phosphatedependent epilepsy

PNPO

Seizures respond to treatment with

supplemental pyridoxal 5-phosphate (PLP)

Pyridoxine-dependent epilepsy
Folinic-acid responsive seizures

ALDH7A1

Seizures respond to treatment with supplemental vitamin B6 and/or folinic acid

Lafora disease

EPM2A, EPM2B

Avoid phenytoin, lamotrigine,

carbamazepine, and oxcarbazepine

Unverricht-Lundborg disease

CSTB

Avoid sodium channel blockers and

GABAergic drugs, which can increase
myoclonus, dementia, and ataxia

West syndrome

TSC1, TSC2,
CDKL5 (STK9),
ARX, STXBP1,
MEF2C

Vigabatrin for infantile spasms with TSC

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS

Genetic Test Results and What They Mean

There are three possible outcomes of genetic testing: a positive result, a negative result, or a
variant of unknown significance (VUS).2

Positive:
A positive result indicates that a disease-causing mutation was identified in the tested individual.
This finding confirms the diagnosis of a particular type of epilepsy and provides valuable information
to the physician and family members about treatment, prognosis, and recurrence risk. All
first-degree relatives (e.g., children, siblings, and parents) of a patient with a positive genetic
test result can then be offered predictive genetic testing. If a family member is found to be
positive for the familial mutation, this individual is also at risk to develop the epilepsy syndrome
and should be referred for further evaluation. It is important to note that there is variability in
symptoms, age of onset, severity, and response to therapeutic agents, even among members
of the same family who have the same genetic mutation causing epilepsy.

Negative:
A negative result in an individual with epilepsy does not rule out a genetically inherited epilepsy
syndrome. Possible reasons for a negative result could be (1) the patient has a mutation in
a gene not included in the testing panel, (2) the patient may have a mutation in a part of an
epilepsy gene that was not covered by the test, or (3) the patient does not have a heritable form
of epilepsy. A negative result obtained in a specific genetic test in an individual with epilepsy
indicates that predictive of asymptomatic family members will not be informative for that same
test, and is not warranted. However, family members of a clinically affected individual with
negative test results may still be at risk for epilepsy syndromes and thus should be evaluated
by a neurologist if indicated.
If an asymptomatic individual is negative for a mutation identified in a family member with epilepsy,
the result is considered a true negative. This indicates that the individual is not at increased
genetic risk for the familial epilepsy syndrome and instead has the same risk as a person in
the general population to develop seizures. Specific clinical monitoring for the development of
seizures is not necessary in individuals with a true negative result.

Variant of Unknown Significance:

One of the most difficult results to interpret is the finding of a variant of unknown clinical significance
(VUS). This situation indicates that the pathogenic role of the variant cannot be clearly established.
In some cases, testing of other family members may help clarify the clinical significance of a
VUS. If other relatives with epilepsy are found to have the same variant, it is more likely that
the variant is disease-causing. The greater the number of affected family members who carry
the VUS, the greater is the likelihood that the VUS is pathogenic. Likewise, if an individual has
apparently sporadic epilepsy, the finding that a VUS is de novo (arose new in that individual and
was not inherited from a parent) indicates that the variant is likely disease-causing.

References:
1. Pong, et al. Developments in molecular genetic diagnostics: An update for the pediatric epilepsy
specialist, Pediatr Neurol (2011) 44:317-327.
2. Pal, et al. Genetic evaluation and counseling for epilepsy. Nat Rev Neurol (2010) 6:445-453.
3. Berg, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the
ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia (2010) 51: 676-685.
4. Deprez, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology (2009)
72:273-281.
5. Baulac, S and Baulac, M. Advances on the genetics of Mendelian idiopathic epilepsies. Neurol Clin
(2009) 27:1041-1061.
6. Macdonald, et al. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol
(2010) 588:1861-1869.
7. Ottman, et al. Genetic testing in the epilepsies Report of the ILAE Genetics Commission. Epilepsia
(2010) 51:655-670.
8. Ramachandran, et al. The autosomal recessively inherited progressive myoclonus epilepsies and their
genes. Epilepsia (2009) 50:29-36.
9. Steinlein, et al. Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci (2004) 5:401-408.

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