Review Article

Developments in Molecular Genetic Diagnostics:

An Update for the Pediatric Epilepsy Specialist
Amanda W. Pong, MD, MSc*, Deb K. Pal, MD, PhD

, and Wendy K. Chung, MD, PhD

The contributions of genetic inuences in both rare and

common epilepsies are rapidly being elucidated, and
neurologists routinely consider genetic testing in the
workup of numerous epilepsy syndromes. Trends in pa-
tient attitudes and developments in clinical molecular
diagnostics will increase interest in, and the availability
of genetic tests for, genetic evaluations of epilepsies. We
review recent and planned developments in clinical
genetic testing platforms, including their indications,
strengths, and limitations. We discuss genome-wide mi-
croarray methods (i.e., methods to detect copy number
variations), karyotypes, and sequence-based testing.
We outline the general approach to genetic evaluations
of epilepsy, emphasizing the importance of clinical eval-
uations, and provide online clinical resources. Finally,
we present potential social, legal, and nancial barriers
to genetic evaluations, and discuss concerns regarding
clinical utility and recurrence risk. This review pro-
vides a practical overview of molecular diagnostics
for the neurologist in the genetic evaluation of epilepsies
in 2011. 2011 Elsevier Inc. All rights reserved.
Pong AW, Pal DK, Chung WK. Developments in molecular
genetic diagnostics: an update for the pediatric epilepsy
specialist. Pediatr Neurol 2011;44:317-327.
Introduction
The contributions of genetic inuences in both rare and
common epilepsies are rapidly being elucidated, and neu-
rologists routinely consider genetic testing in the workup
of numerous epilepsy syndromes. Simultaneously, trends
in consumer attitudes and developments in clinical
molecular diagnostics will increase the interest in, and
the demand for, genetic evaluations of epilepsies, although
the role of testing is still debated [1-3]. Given the uneven
access to clinical genetics services outside major
academic medical centers, the burden of this demand will
largely fall upon the neurologist who diagnoses and
manages the patient with epilepsy. Thus, neurologists
need to be conversant with the technologies and
principles underpinning genetic evaluation and counseling.
This review is intended to (1) bring the reader up to date
with recent and planned developments in commercial test-
ing platforms, and (2) discuss their indications, strengths,
and limitations. Moreover, we outline the general approach
to genetic evaluations of epilepsy, emphasizing the essen-
tial clinical nature of the process and potential barriers to
testing. This review provides a practical overview of
molecular diagnostics for the neurologist in the genetic
evaluation of epilepsies in 2011.
Developments in Molecular Diagnostics
Clinical genetic testing is complicated in disorders for
which several different genetic or nongenetic etiologies in-
volve the same clinical presentation. This circumstance ap-
plies to neurologic conditions such as mental retardation,
autism, and epilepsy [4]. Although several rare Mendelian
forms of epilepsy were elucidated, they account for <1%of
patients with epilepsy. About 40%of epilepsies are thought
to manifest a complex genetic inheritance due to a combi-
nation of several genetic variants acting together, but at
present, tests for these variants are not offered clinically,
and do not have obvious clinical utility.
Genetic testing for epilepsy is often not straightforward
because the total number of genes in a differential diagno-
sis is often large. Mutations are often private (i.e.,
unique to each family), necessitating comprehensive
From the *Department of Neurology, Neurological Institute, Columbia
University Medical Center, Columbia University, New York, New York;

Department of Clinical Neuroscience, Institute of Psychiatry, Kings

College London, London, United Kingdom;

Department of Psychiatry,
Columbia University Medical Center, New York, New York; and

Division of Molecular Genetics, Department of Pediatrics, Columbia

University Medical Center, Columbia University, New York, New York.
Communications should be addressed to:
Dr. Pong; Department of Neurology, Neurological Institute; Columbia
University Medical Center, Columbia University; 180 Fort Washington
Avenue; Harkness Pavilion, 5th Floor; New York, NY 10032.
E-mail: awp4@columbia.edu
Received July 19, 2010; accepted January 31, 2011.
2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.pediatrneurol.2011.01.017
0887-8994/$ - see front matter
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 317
sequence analysis of the relevant genes. Evolving technol-
ogies will allow for interrogations of larger amounts of
DNA sequences and of copy numbers for detecting gene
deletions and duplications, and will transform conven-
tional methods of clinical investigation by permitting the
parallel evaluation of multiple genetic etiologies [2].
In rare circumstances, knowledge of the etiology of sei-
zures affects their clinical management (e.g., glucose trans-
porter Type 1 deciency syndrome, pyridoxine-dependent
seizures, and Dravet syndrome). With the possibility of
targeted therapy based on the molecular etiology and
mutation type (e.g., chaperones for missense mutations, or
agents mediating a read-through of premature termination
mutations), the importance of accurately deningthe specic
gene and mutation causing a patients epilepsy may increase.
In addition, a genetic etiology for the epilepsy must be de-
ned, to provide families with accurate information about
risks of recurrenceandeffective reproductive options, includ-
ingprenatal diagnosis andpreimplantationgenetic diagnosis.
Molecular Genetic Diagnostics in the Age of Rapidly
Evolving Technologies
Whole-genome screening to survey the genome for copy
number variations (deletions and duplications) is equivalent
to performing a genome-wide uorescence in situ hybridiza-
tion study (Table 1). Oligonucleotide microarrays are readily
available through a number of clinical laboratories [5].
Genome-wide microarrays range in probe density from
40,000 to over 1,000,000 oligonucleotide probes, to generate
a high-resolution molecular karyotype. These arrays will
likely replace the karyotype as a rst-line test because of
the improved resolution of a chromosome microarray (rou-
tinely, at least <0.5 Mb) relative to a karyotype (>5 Mb). In
fact, in the new consensus statement, chromosome microar-
rays are recommended as the rst-tier test in patients with un-
explaineddevelopmental delay, intellectual disability, autism
spectrumdisorders, or multiple congenital anomalies [6]. Al-
though a karyotype is generally less informative, it is still
complementary, because only a karyotype can provide struc-
tural information about the chromosome (e.g., the location of
duplicated material or ring chromosomes) and identify bal-
anced rearrangements such as balanced translocations.
Laboratories currently use two types of oligonucleotide
chromosome microarrays: (1) one that includes single-
nucleotide polymorphisms or (2) oligonucleotides designed
only to quantify copy number. The advantage of single-
nucleotide polymorphisms oligonucleotide microarray
analysis involves its abilitytodistinguishparental genotypes
and thus detect uniparental disomy for the diagnosis of An-
gelman syndrome, for example, and to detect stretches of
homozygosity that suggest a recessive condition with a ho-
mozygous mutation froma common ancestor. Oligonucleo-
tide microarray analysis is routinely covered by insurance
companies, andhas approximatelya yieldof 10-15%inchil-
dren with mental retardation and a normal karyotype [7],
with increasing yield as the severity of mental retardation in-
creases. Other clinical features that increase the yield in-
clude dysmorphic features, intrauterine growth restriction,
failure to thrive, birth defects, and a history of recurrent mis-
carriages in the parents (usually associated with one parent
who is a balanced translocation carrier).
With recent advances in chromosome microarray analy-
sis, we are only now beginning to dene many novel ge-
netic syndromes associated with recurrent deletions and
duplications, such as the 1p36 deletion associated with ep-
ilepsy [8], 16p11 microdeletion syndrome [9], and the
16p11 duplication syndrome associated with autism [10].
With increasing experience, these new syndromes will be
better dened, and additional details will be available
regarding associated clinical features, range of severity of
signs, and penetrance.
Notably, we are beginning to dene normal genomic ar-
chitecture, including the location and frequency of benign
polymorphic deletions and duplications that are present
throughout the genome. Therefore, to receive a test report
from a chromosome microarray analysis that identies a
deletion or duplication variant of unknown clinical signif-
icance is not uncommon. In such cases, whether this copy
number variant constitutes a normal benign polymorphism
or a pathogenic, disease-associated mutation is not clearly
established [11]. To distinguish between these two possibil-
ities, the parents should be tested for the copy number var-
iant. If both parents are normal, the copy number variant is
interpreted as disease-associated, because the copy number
variant has arisen de novo fromunaffected parents. If one of
the parents is affected, the copy number variant may be
pathogenic if it is inherited from an affected parent. Many
copy number variants are associated with different neuro-
psychiatric phenotypes, so the offspring and parent may
both be affected but discordant for the phenotype. With
additional characterization of populations, the number of
test reports with variants of unknown clinical signicance
should decrease signicantly.
Genome-wide microarrays are not generally designed to
detect small genomic alterations of less than approximately
200 kb. However, targeted exon arrays are being devel-
oped to detect small deletions or duplications involving
only portions of single genes associated with a specic phe-
notype [12]. These types of mutations are generally on the
order of 500-100,000 base pairs, and are routinely invisi-
ble to molecular methods that rely on polymerase chain re-
action amplication followed by sequence analysis.
Increasingly, exon arrays have been designed to comple-
ment sequence-based tests [12]. This test is particularly use-
ful for recessive disorders in which only one mutation is
identied by sequence analysis, suggesting the presence
of another mutation not detected by sequencing methods.
Sequence-based testing for specic genes is widespread
(see www.genetests.org). In general, the cost of a sequenc-
ing test is linearly related to the size and number of genes.
Anewgeneration of sequencing instruments was introduced,
based on highly parallel data generation, and such instru-
ments can analyze 200 genes per test or more. Next-
318 PEDIATRIC NEUROLOGY Vol. 44 No. 5
generation instruments generate massive amounts of se-
quence data and greatly reduce the cost of sequencing per
base, compared with traditional capillary sequencing. This
enhanced capacity offers great potential to analyze large
amounts of DNA for mutations, and will facilitate the devel-
opment of genetic test panels for multiple types of mental re-
tardation and epilepsies. Several laboratories have begun
offering panels of tests for mental retardation, some of which
are focused on X-linked inheritance. Initially, the limited
characterizations of the normal genetic variation for the
genes in these panels may limit the initial clinical utility of
these tests, yielding many test results of variants of unknown
clinical signicance, but testing will improve as additional
normal individuals are genetically sequenced as part of re-
search studies, and as clinical testing laboratories gain expe-
rience with these genes.
The capture and sequencing of subgenomes, such as the
entire exome, or even entire genomes, are underway in
research laboratories [13,14], and may enter clinical
diagnostic laboratories within the next 3 years as the cost of
sequencing decreases and databases of normal references
sequences become available for comparison. When such
testing becomes available, it will completely change the
genetic diagnostic landscape, and should greatly facilitate
diagnostic testing. However, advances in biomedical
informatics will be necessary to analyze sequence data
quickly and robustly before these tests are ready for clinical
use. Initially when such tests are launched, they are likely
to identify many variants of unknown signicance, as well
as many incidental genetic mutations not directly related
to the patients epilepsy but related to predispositions for
other diseases, including cancer, heart disease, and
diabetes. Patients and families will need to grapple with
new ethical and personal questions regarding how much of
this information they want to know [15,16]. Because this
landscape is likely to change radically in the near future,
families for whom a genetic diagnosis is not immediately
necessary should consider postponing expensive genetic
testing for single-gene disorders of low diagnostic yield,
and waiting until more comprehensive sequencing tests are
clinically available [3] (Table 1).
Clinical Indications for Genetic Testing
Genetic testing in a symptomatic patient with epilepsy is
described as diagnostic, whereas it is termed predictive
if a patient is asymptomatic but at increased future risk of
seizures. For a patient who presents with epilepsy, with or
without additional signs suchas developmental delayor dys-
morphism, genetic testing would be considered diagnos-
tic. Most genetic testing for epilepsy in children will be
diagnostic. If not all patients with a particular genetic sus-
ceptibilitydevelop seizures, the condition is termed incom-
pletely penetrant, and genetic testing alone will not
accurately predict which patients will develop seizures,
thereby limiting the clinical utility of these conditions.
The clinical indications for genetic testing were recently
reviewed [2], and are the subject of ongoing debate. The
utility of genetic information rests on the specic nding it-
self as well as our understanding of the mutation and its re-
lationship with the phenotype [3]. In particular clinical
scenarios, the utility of identifying a specic cause for a pa-
tients epilepsy may clarify the prognosis, assist with treat-
ment and management (e.g., the use of a ketogenic diet in
glucose transporter Type 1 deciency syndrome) [17-19],
and, for the parents and the proband, clarify the risk of
a disease in family members and future children.
Identifying a specic genetic etiology may save a patient
from further diagnostic evaluation and potentially
invasive testing, and should shorten the diagnostic
odyssey that many families endure. However, in the
majority of patients with epilepsy, the results of genetic
testing will not change their medical treatment [1,2].
Approach to Genetic Evaluation
A genetic evaluation consists of reviewing the patients
history and medical records, and documenting at least
a three-generation pedigree to identify patterns of inheri-
tance. A family history should focus on seizures, ts,
syncope, blackouts, speech and language disorders, learning
disabilities, autism, mental retardation, and other psychiat-
ric conditions in the family. The history should include cur-
rent ages and ages of onset, ancestral origins, consanguinity,
and outcomes of all pregnancies. Asking parents to contact
other family members is often helpful in ascertaining com-
plete and accurate information, because a full pedigree may
not be obtained during the rst interview. A physical exam-
ination should include assessment of growth, birth defects,
dermatologic ndings, and dysmorphic features, in addition
to the neurologic examination.
Electroencephalograms (while both awake and asleep)
and an epilepsy protocol cranial magnetic resonance
imaging and spectroscopy are considered essential for eval-
uation under most circumstances [2]. Genetic testing may
consist of the examination of metabolites in the urine,
blood, and cerebrospinal uid; enzymatic activity in sam-
ples of blood, broblasts, or muscle; molecular genetic
Table 1. Comparison of genetic testing platforms
Test Resolution Types of Mutations Detected
Chromosome microarray analysis 200 kb Deletions and duplications and uniparental disomy using
single-nucleotide polymorphisms arrays
Exon array Approximately 500-1000 bp Deletions and duplications
Sequencing 1 bp Changes in single or small numbers of nucleotides
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 319
testing; and cytogenetics, including a chromosome micro-
array. In general, most molecular genetic tests can be per-
formed noninvasively on blood. Additional investigations
that may be helpful include neuropsychologic testing and,
for presurgical evaluation, an electroencephalogramidenti-
cation of the seizure onset zone and radionuclide scanning
(positron emission testing and single-photon emission com-
puted tomography).
An updated list of the genetic tests available and the lab-
oratories performing testing is available at genetests.org,
which provides an excellent resource for clinicians. Perti-
nent information is available through the United Kingdom
Genetic Testing Network (http://www.ukgtn.nhs.uk/gtn/
Home), which has compiled gene dossiers for a handful
of testable conditions, including Dravet syndrome.
Specically for mutations in SCN1A, an updated database
is available online (http://www.molgen.ua.ac.be/SCN1
Amutations/) that includes all genetic variations reported
in the literature and submitted directly to the website. For
the patient facing a genetic diagnosis, the United States Na-
tional Library of Medicine provides a comprehensive home
reference for understanding genetic conditions, inheritance
patterns, and related resources (http://ghr.nlm.nih.gov).
A commonly used patient resource for all aspects of
epilepsy care is available at Epilepsy.com.
In the United States, only Clinical Laboratory Improve-
ment Amendments-certied clinical laboratories should
be used for clinical diagnoses of patients. One drawback
of commercially available genetic tests involves their lack
of epidemiologic information about the frequency of muta-
tions or the full spectrum of a disease [3,20]. The data
regarding the yield of several molecular analyses, given
particular clinical characteristics, were reviewed as they
apply to children before age 1 year and older age groups
[3,21] (Table 2).
In addition to our incomplete understanding of the epide-
miology and clinical utility of diagnostic genetic testing, an-
other relevant concern involves our limited knowledge about
the potential ethical, legal, and social implications of genetic
testing in the epilepsies [15]. Shostak and Ottman provided
a concise reviewof the social science perspectives of genetic
information, highlighting the potential for stigma, distress,
adverse labeling, andnoncondentialitythat exists inthe set-
ting of inadequate safeguards against discrimination [15]. In
light of these ethical, legal, and social implications, genetic
testing should always be performed with the patients
consent, or parental consent in the case of minors. A team
approach, including a genetic counselor and social worker,
is recommended throughout the process of evaluation.
Potential Barriers to Testing
There are multiple potential and actual barriers to diag-
nostic genetic testing in epilepsy. The major barrier is often
nancial. Many of these tests cost hundreds to several thou-
sand United States dollars each, some portion of which
may be covered by insurance companies for diagnostic
but not always predictive indications. Genetic information
may lead to psychological and social consequences, in-
cluding blame or guilt, stigmatization, and feelings of iso-
lation [15]. As with other heritable conditions, patients
may be concerned about possible discrimination against
themselves and other family members. In May 2008, the
federal Genetic Information Non-Discrimination Act was
passed by the United States Congress, and began to take
effect in May 2009. The Genetic Information Non-
Discrimination Act protects Americans from having their
health insurance rates raised, being denied health insurance
coverage, or being denied a job or job promotion on the
basis of a genetic predisposition (i.e., predictive genetic
testing). This protection does not extend to life insurance,
disability insurance, or long-term care insurance. Some
states also passed additional legislation that affords more
extensive protection to patients. The Genetic Information
Non-Discrimination Act should provide additional reassur-
ance to families seeking genetic testing.
Attitudes Toward Genetic Testing
Not much is known about attitudes toward genetic testing
for epilepsy. Those concerned about the reproductive risk of
recurrence for themselves or their family members may be
more likely to pursue genetic testing. Recent work indicates
that, for adults with epilepsy, concerns about the ability to
care for offspring or about passing epilepsy on to a child
were associated with the decision to have fewer children
[22]. Families of children with more severe epilepsy or co-
morbidities, and families with more than one affected fam-
ily member, may be more interested in genetic testing
because the risks and burden of having another affected
child are higher. Some families may be specically inter-
ested in genetic testing that alters the course of treatment,
but may be ambivalent toward genetic testing that will not
change the treatment. Many families seek a diagnosis to
clarify a prognosis and nd an appropriate support group
of other families with similarly affected children. However,
the relationships between the increase in diagnostic genetic
testing and specic clinical, social, economic, and demo-
graphic factors have not yet been studied.
Recurrence Risk in Families, and Reproductive Options
The issue of risk of recurrence for the parents, siblings,
and other family members, as well as the patient per se, is
often of concern to the family. Usually, the immediate con-
cern involves the risk of recurrence for the parents if chil-
dren are young. Many severe pediatric neurogenetic
conditions are the result of de novo or spontaneous muta-
tions. If this result is proven after testing the parents blood,
then the risk of recurrence for the parents is <1%, and any
recurrence is attributable to undetectable gonadal mosai-
cism. In such families, prenatal testing with chorionic vil-
lus sampling or biopsy or amniocentesis may constitute an
appropriate route, and provides reassurance to parents.
320 PEDIATRIC NEUROLOGY Vol. 44 No. 5
Table 2. Common pediatric epilepsy conditions and relevant diagnostic genetic tests
Prominent Clinical
Features Clinical Presentation
Diagnostic Molecular
Genetic Tests (%Yield)
Implications for
Seizure Treatment
De Novo vs Inherited
(Mode of Inheritance) References
Onset before age 1 year
West syndrome Infantile spasms,
hypsarrhythmia,
encephalopathy
Karyotype, aCGH,
Consider: TSC1, TSC2,
CDKL5 (STK9), ARX,
STXBP1, MEF2C
VGB for infantile spasms
with TSC
Various [28-31]
Dravet syndrome Early onset prolonged/
hemiclonic sz, febrile
status epilepticus,
myoclonic, atypical
absence, partial sz.
SCN1A (#90%),
GABRG2, SCN9A
VPA, CLB, STP, LEV,
TPM. Avoid PHT,
CBZ, LTG.
De novo (AD) [1,32-35]
Ohtahara syndrome Suppression burst on
electroencephalogram,
tonic sz
STXBP1, ARX NS Various [31,36,37]
Glucose transporter
Type I deciency
syndrome
Early-onset refractory sz,
movement disorders,
ataxia, progressive
encephalopathy,
acquired microcephaly,
spasticity
SLC2A1 (91%) KGD Majority are de novo
(AD)
[17,18,38]
Pyridoxine dependent
seizures
Vitamin B6-responsive sz ALDH7A1 Vitamin B
6
Inherited (AR) [39,40]
Biotinidase deciency Rash, alopecia, ataxia,
DD, sz
BTD Biotin Inherited (AR) [41,42]
Nonketotic
hyperglycinemia
Apnea, sz, DD,
hypertonia, early
mortality, CSF+
GLDC (70-75%), AMT
(20%), GCSH (<1%)
Sodium benzoate, NMDA
receptor antagonists.
Avoid VPA.
Inherited (AR) [43]
Leigh disease Neurodegenerative
condition with high
phenotypic variability
NARP mtDNA NS Inherited (maternal) [44]
Menkes disease Regression at 3 months,
hypotonia, sz, steely
hair, failure to thrive,
early mortality
ATP7A NS Inherited (X-linked
recessive)
[45,46]
Alexander disease Megalencephaly, sz, DD,
spasticity
GFAP NS De novo (AD) [47]
Molybdenum cofactor
deciency
Microcephaly and
refractory epilepsy,
high urinary
thiosulfates
MOCS1, MOCS2, GEPH NS Inherited (AR) [48,49]
Epilepsy in females
with mental
retardation
Early-onset sz, autism,
DD, in affected
females linked by
unaffected males
PCDH19 NS Majority inherited (X-
linked disorder
affecting heterozygous
females, and sparing
hemizygous males)
[50-52]
Benign syndromes
Benign familial
neonatal seizures
Neonatal sz at
approximately 3 days
of age, resolution at <1
month of age,
generalized or focal
tonic-clonic seizures,
normal development
KCNQ2, KCNQ3 NS Various (AD) [53]
Benign familial
neonatal-infantile
seizures (BFNIS)
Sz from age 2 days to 6
months, normal
development
SCN2A NS Inherited (AD) [54]
Onset in early to mid
childhood
Creatine deciency
syndromes
DD, sz, MRS+, autism SLC6A8, GAMT, GATM Oral creatine (GAMT,
AGAT)
Inherited: GAMT/GATM
(AR), SLC6A8 (X-
linked)
[55]
Autosomal dominant
nocturnal frontal
lobe epilepsy
Seizures arising from
sleep, prominent motor
manifestations
CHRNA4, CHRNB2,
CHRNA2
NS Inherited (AD) [56]
Alpers-Huttenlocher
syndrome
Progressive
encephalopathy,
refractory sz, hepatic
failure, poliodystrophy
POLG1 Avoid VPA (liver failure) Inherited (AR) [57,58]
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 321
Table 2. Continued
Prominent Clinical
Features Clinical Presentation
Diagnostic Molecular
Genetic Tests (%Yield)
Implications for
Seizure Treatment
De Novo vs Inherited
(Mode of Inheritance) References
Autosomal dominant
partial epilepsy
with auditory
features
Ictal auditory symptoms
and receptive aphasia,
secondary
generalization, benign
course
LGI1 (33%) NS Inherited (AD) [59-61]
Febrile seizures
Genetic epilepsy and
febrile seizures
plus
Onset of febrile seizures
at <1 year of age,
persistence beyond age
6 years, evolution to
mixed sz types
SCN1A (11.5%), SCN2B
(4.1%), GABRG2
(<1%)
NS Inherited (AD) [2,62]
Myoclonus
Neuronal ceroid-
lipofuscinosis
Intellectual and motor
deterioration, sz, visual
loss, early mortality
PPT1, TPP1, CLN3,
CLN5, CLN6, MFSD8,
CLN8, CTSD
NS Inherited (AR) [63]
MELAS Lactic acidosis,
ophthalmoplegia, sz,
stroke-like episodes,
ragged red bers
Mitochondrial DNA
evaluation
Avoid VPA Inherited (maternal) [64,65]
MERRF Childhood onset
myoclonus,
generalized sz, ataxia,
weakness, dementia,
hearing loss, optic
atrophy,
cardiomyopathy
Mitochondrial DNA
evaluation
Avoid VPA, PHT, LTG,
CBZ, OXC
Inherited (maternal) [64,66]
Baltic myoclonus Individuals in late
childhood or
adolescence with
photosensitive
myoclonus, sz, ataxia
EPM1 (cystatin B) Avoid PHT, LTG, CBZ,
OXC, GBP, TGB, VGB
Inherited (AR) [67]
Lafora disease Progressive myoclonus,
myoclonic epilepsy,
absences, dementia
EPM2A, EPM2B Avoid PHT, LTG, CBZ,
OXC
Inherited (AR) [63,68]
DD dysmorphism Karyotype, aCGH NS Mixed [69]
Rett syndrome Regression then
stagnation, onset at <18
months of age, loss of
purposeful hand
movements, acquired
microcephaly
MECP2 (93%) NS De novo (X-linked) [70,71]
Atypical Rett
syndrome
Early-onset seizure
variant of Rett
syndrome, infantile
spasms
CDKL5 (9-28%) NS De novo (X-linked
dominant)
[72,73]
Angelman syndrome DD onset at >6 months of
age, ataxia,
tremulousness,
happy appearance,
microcephaly, sz
DNA methylation
analysis (15q11.2-q13)
(78%)
NS Various [74]
Prader-Willi syndrome Hypotonia, excessive
eating, obesity, DD, sz,
hypogonadism
DNA methylation
analysis (15q11.2-q13)
(99%)
NS Various [75]
Wolf-Hirschorn
syndrome
Craniofacial
abnormalities, prenatal
onset of growth
retardation, DD, sz
4p16.3 (50-60%) NS Majority are de novo [76]
1p36 deletion
syndrome
Craniofacial
abnormalities, DD,
hypotonia, structural
brain abnormalities,
renal/cardiac defects,
infantile spasms
1p36 NS Majority are de novo [8,77]
Ring chromosome 20
syndrome
DD, sz, nonconvulsive
status
Karyotype NS De novo [69,78]
322 PEDIATRIC NEUROLOGY Vol. 44 No. 5
Table 2. Continued
Prominent Clinical
Features Clinical Presentation
Diagnostic Molecular
Genetic Tests (%Yield)
Implications for
Seizure Treatment
De Novo vs Inherited
(Mode of Inheritance) References
Inversion duplication
15 syndrome
DD, refractory sz, central
hypotonia, autism,
infantile spasms
G-C banding cytogenetics
with FISH analysis,
aCGH if positive
NS Various [79-81]
Abnormal brain magnetic
resonance imaging
Tuberous sclerosis
complex
DD, sz, infantile
spasms, lesions
involving skin, brain,
kidney, heart, lungs,
and eyes
TSC1, TSC2 (70-80%) VGB for infantile spasms Various (AD) [82,83]
Neurobromatosis
type 1
Cafe-au-lait lesions,
neurobromas,
freckling, optic glioma,
Lisch nodules, sz
NF1 (>95%) NS Various (AD) [83-85]
Lissencephaly Miller-Dieker syndrome
and isolated posterior
predominant
lissencephaly sequence
LIS1 (PAHAH1B1) NS De novo (AD) [86-88]
Isolated anterior
predominant
lissencephaly in males
DCX (12%) NS Various (X-linked) [87,89,90]
X-linked lissencephaly
with abnormal genitalia
ARX NS Inherited (X-linked
recessive)
[87,91]
Mild lissencephaly with
cerebellar hypoplasia,
DD, hypotonia, sz
RELN NS Inherited (AR) [87,89,92]
Subcortical band
heterotopia
Variable DD, epilepsy in
females
DCX (53-84%) NS Various (X-linked) [87,89,90,93,94]
Heterotopia Periventricular nodular,
subcortical, or marginal
glioneuronal, DD, sz
FLNA, ARFGEF2 NS Various (X-linked);
inherited (AR)
[87,95]
Polymicrogyria Bilateral perisylvian
form: DD, sz,
pseudobulbar palsy
SRPX2 NS Various (AD, AR, X-
linked)
[87,96-100]
Bilateral frontoparietal
form: DD, esotropia,
sz, cerebellar and
pyramidal signs
GPR56 NS Inherited (AR) [87,96,101]
Dentatorubro-
pallidoluysian
atrophy
Progressive ataxia,
myoclonus, sz,
regression, cerebellar
and brainstem atrophy
Atrophin-1 (ATN1) NS Inherited (AD) [102,103]
Metachromatic
leukodystrophy
Progressive hypertonia,
extremity pain,
regression and
dementia, with
leukodystrophy
ARSA (arylsulfatase A
deciency)
NS Inherited (AR) [104]
Abbreviations:
aCGH = Array comparative genomic
hybridization
AD = Autosomal dominant
AR = Autosomal recessive
CBZ = Carbamazepine
CLB = Clobazam
CSF+ = Cerebrospinal uid positive
DD = Developmental delay
FISH = Fluorescence in situ hybridization
GBP = Gabapentin
KGD = Ketogenic diet
LEV = Levetiracetam
LTG = Lamotrigine
MELAS = Mitochondrial myopathy,
encephalopathy, lactic acidosis,
and stroke-like episodes
MERRF = Myoclonic epilepsy with
ragged-red bers
MRS = Magnetic resonance
spectroscopy
NMDA = N-methyl D-aspartate
NS = Not signicant
OXC = Oxcarbazepine
PHT = Phenytoin
STP = Stiripentol
sz = Seizures
TGB = Tiagabine
TPM = Topiramate
VGB = Vigabatrin
VPA = Valproate
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 323
The risk of recurrence is signicant if (1) a parent is a bal-
anced chromosomal translocation carrier; (2) a mother is the
carrier for anX-linkedcondition; (3) a mother is the carrier of
a mitochondrial mutation; (4) both parents are carriers for an
autosomal recessive condition; or (5) a parent carries an au-
tosomal dominant disorder (Table 2). Parents desiring addi-
tional unaffected children have multiple options, including
(1) adoption, (2) the use of a donor egg or donor spermto re-
move the genetic contribution of the parent transmitting the
mutation, (3) prenatal testing (either chorionic villus sam-
pling at 10-12 weeks of gestation, or amniocentesis after
16 weeks of gestation), or (4) preimplantation genetic diag-
nosis, in which only embryos without the familial mutation
are transferred into the uterus. Prenatal diagnosis without
considering the termination of a pregnancy may be helpful
in certain metabolic disorders for which immediate neonatal
management is effective and can avoid neurologic damage.
Donor sperm are more accessible than donor eggs. Donors
of sperm or eggs should not be genetically related to the
parents, unless they do not carry the familial mutation.
Preimplantation genetic diagnosis is an appealing option
for couples because it avoids the difculty of terminating
an at-risk fetus. However, it requires in vitro fertilization,
and has only a 25% success rate/cycle in couples without
fertility issues [23,24], and may not be covered in part or at
all by insurance. Preimplantation genetic diagnosis can
signicantly reduce risks, but is associated with rare errors
in approximately 2% of cases [23]. Thus, although preim-
plantation genetic diagnosis usually avoids the necessity to
terminate an affected pregnancy, the process should be care-
fully considered by couples before initiation. Preimplanta-
tion genetic diagnosis is available in the United States, but
not in all countries.
Attitudes toward these family-planning options vary by
culture, based in part on religious beliefs and the accept-
ability of terminating a pregnancy [25]. For extended fam-
ily members, the risk should rst be dened by genetic
testing for familial mutations [2]. For those who carry a fa-
milial mutation, similar reproductive options are available.
Patients with epilepsy who are able and interested in
having children should be carefully counseled about their
options and about the possible teratogenic effects of med-
ications before conception [26]. Although a genetic condi-
tion may have been de novo in the affected patient and
associated with a benign family history, the risk of recur-
rence may be signicant (as high as 50%) in the children
of an affected de novo mutation carrier (Table 3).
Mutations encoded within the mitochondrial genome
pose a unique problem in terms of risks of recurrence at-
tributable to heteroplasmy (a mixture of mitochondrial ge-
notypes in the cell). Risk cannot be accurately predicted for
a woman carrying a mitochondrial mutation, nor is prenatal
testing accurate, because a differential mitochondrial mu-
tation load by tissue may not be accurately reected in
the placenta during chorionic villus sampling or in amnio-
cytes. For women in such families with mitochondrial
epilepsies (such as myoclonic epilepsy with lactic acidosis
and strokes), the only way to guarantee the avoidance of
recurrence is to use a donor egg [27].
Discussion
The clinical utility of genetic testing in the epilepsies
varies widely, depending on the clinical scenario. In our
previous work, we evaluated the specic utility of genetic
testing in ve common epilepsy scenarios: Dravet and
related syndromes, infantile spasms, brain malformations,
mental retardation or dysmorphic features, and the com-
mon idiopathic epilepsies [2]. The specic epidemiologic
test properties of epilepsy are largely unknown, particu-
larly in younger age groups [21]. A model for evaluating
the analytic validity, clinical validity, clinical utility, and
accompanying ethical, legal, and social implications for
genetic tests was developed by the United States Centers
Table 3. Risk of recurrence and effective reproductive options available to avoid recurrence
Mode of Inheritance Risk of Recurrence Reproductive Options
Balanced translocation carrier Variable, depending on gender of parent and
exact translocation
Donor sperm
Donor egg
Prenatal testing
Preimplantation genetic diagnosis
X-linked 50% of males
Rarely in females
Donor egg
Prenatal testing
Preimplantation genetic diagnosis
Mitochondrial Variable and unpredictable Donor egg
Autosomal recessive 25% Donor egg
Donor sperm
Prenatal testing
Preimplantation genetic diagnosis
Autosomal dominant 50% Donor egg
Donor sperm
Prenatal testing
Preimplantation genetic diagnosis
Complex Empiric None available
324 PEDIATRIC NEUROLOGY Vol. 44 No. 5
for Disease Control and Prevention, the National Ofce of
Public Health Genomics, and the Foundation for Blood
Control, and was presented by the International League
Against Epilepsy as a tool in the approach to specic tests
for epilepsy [3].
So far, a genetic diagnosis affects the choice of treatment
and clinical outcomes in only a small number of genetic ep-
ilepsy conditions: glucose transporter Type 1 deciency
[18], Dravet syndrome, West syndromewithtuberous sclero-
sis complex, and pyridoxine-dependent epilepsy [2]. Some
of these diagnoses may be established on clinical grounds,
e.g., seizure semiology, medical history, or metabolic test-
ing, before evaluation with conrmatory genetic testing.
The number of potentially treatable metabolic and genetic
conditions presenting with epilepsy in childhood continues
to grow. Although the availability and accessibility of spe-
cic genetic tests are likely to increase in the near future,
clinical management still rests largely on patient ndings
from examinations, history, and other investigations.
The molecular diagnostic genetic testing platforms re-
viewedherewill become increasinglyrelevant inthe diagnos-
tic evaluation of children with epilepsy. Novel genetic
syndromes are being dened through advances in chromo-
somal microarray analysis. Oligonucleotide microarrays
nowcomplement the structural informationfromkaryotypes,
and provide much higher resolution than karyotypes in
identifying deletions and duplications. Targeted exon arrays
allowfor the detection of small genomic alterations invisible
to genome-wide microarrays, and complement sequence-
based tests for analyses of single genes. Sequence-based
testing for specic genes is widely available, and will be mul-
tiplexed by clinical indications to improve clinical diagnoses.
Molecular genetic diagnostics are rapidly evolving in step
with the discovery of new genetic syndromes, and should re-
duce the time to diagnosis, so that efforts can be focused on
treatment rather than diagnosis. Thus uency in these
methods is essential for the neurologist in the 21st century.
D.K.P. was supported by a European Union Marie Curie Award, the Wa-
terloo Foundation, the Charles Sykes Epilepsy Research Trust, the Na-
tional Institute for Health Research Comprehensive Biomedical
Research Centre at Guys and St. Thomas Hospital National Health Ser-
vice Trust, and the National Institute for Health Research Specialist Bio-
medical Research Centre at Maudsley Hospital. The authors acknowledge
the assistance of Dr. Masanori Takeoka in editing the tables.
References
[1] Delgado-Escueta AV, Bourgeois BF. Debate: Does genetic infor-
mation in humans help us treat patients? ProGenetic information in hu-
mans helps us treat patients. ConGenetic information does not help at
all. Epilepsia 2008;49(Suppl. 9):13-24.
[2] Pal DK, Pong AW, Chung WC. Genetic evaluation and genetic
counseling for epilepsy. Nat Rev Neurol 2010;6:445-53.
[3] Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilep-
siesReport of the ILAE Genetics Commission. Epilepsia 2010;51:
655-70.
[4] Ferraro TN, Dlugos DJ, Buono RJ. Role of genetics in the diag-
nosis and treatment of epilepsy. Expert Rev Neurother 2006;6:1789-800.
[5] Hoppman-Chaney N, Peterson LM, Klee EW, Middha S,
Courteau LK, Ferber MJ. Evaluation of oligonucleotide sequence capture
arrays and comparison of next-generation sequencing platforms for use in
molecular diagnostics. Clin Chem 2010;56:1297-306.
[6] Miller DT, Adam MP, Aradhya S, et al. Consensus statement:
Chromosomal microarray is a rst-tier clinical diagnostic test for individ-
uals with developmental disabilities or congenital anomalies. Am J Hum
Genet 2010;86:749-64.
[7] Edelmann L, Hirschhorn K. Clinical utility of array CGH for the
detection of chromosomal imbalances associated with mental retardation
and multiple congenital anomalies. Ann N YAcad Sci 2009;1151:157-66.
[8] Bahi-Buisson N, Guttierrez-Delicado E, Soufet C, et al. Spectrum
of epilepsy in terminal 1p36 deletion syndrome. Epilepsia 2008;49:509-15.
[9] Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at
16p13.11 predispose to a diverse spectrum of sporadic epilepsy syn-
dromes. Am J Hum Genet 2010;86:707-18.
[10] Weiss LA, Shen Y, Korn JM, et al. Association between micro-
deletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;
358:667-75.
[11] Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy
number variation in epilepsy: Novel susceptibility loci in idiopathic gen-
eralized and focal epilepsies. PLoS Genet 2010;6:e1000962.
[12] TayehMK, ChinEL, Miller VR, BeanLJ, Coffee B, HegdeM. Tar-
geted comparative genomic hybridization array for the detection of single-
and multiexon gene deletions and duplications. Genet Med 2009;11:232-40.
[13] Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole
exome capture and massively parallel DNA sequencing. Proc Natl Acad
Sci USA 2009;106:19096-101.
[14] Lupski JR, Gonzaga-Jauregui C, Rio Deiros D, et al. Whole-ge-
nome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
N Engl J Med 2010;362:1181-91.
[15] Shostak S, Ottman R. Ethical, legal, and social dimensions of
epilepsy genetics. Epilepsia 2006;47:1595-602.
[16] Klitzman R. Views of discrimination among individuals con-
fronting genetic disease. J Genet Couns 2010;19:68-83.
[17] De Vivo DC, Triletti RR, Jacobson RI, Ronen GM,
Behmand RA, Harik SI. Defective glucose transport across the blood-
brain barrier as a cause of persistent hypoglycorrhachia, seizures, and de-
velopmental delay. N Engl J Med 1991;325:703-9.
[18] Wang D, Pascual JM, Yang H, et al. Glut-1 deciency syndrome:
Clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57:111-8.
[19] Klepper J, Diefenbach S, Kohlschutter A, Voit T. Effects of the
ketogenic diet in the glucose transporter 1 deciency syndrome. Prosta-
glandins Leukot Essent Fatty Acids 2004;70:321-7.
[20] Greenberg DA, Pal DK. The state of the art in the genetic
analysis of the epilepsies. Curr Neurol Neurosci Rep 2007;7:320-8.
[21] Deprez L, Jansen A, De Jonghe P. Genetics of epilepsy syn-
dromes starting in the rst year of life. Neurology 2009;72:273-81.
[22] Helbig KL, Bernhardt BA, Conway LJ, Valverde KD, Helbig I,
Sperling MR. Genetic risk perception and reproductive decision making
among people with epilepsy. Epilepsia 2010;51:1874-7.
[23] Harper JC, Boelaert K, Geraedts J, et al. ESHRE PGD Consor-
tium data collection V: Cycles from January to December 2002 with preg-
nancy follow-up to October 2003. Hum Reprod 2006;21:3-21.
[24] Feyereisen E, Steffann J, Romana S, et al. Five years experience
of preimplantation genetic diagnosis in the Parisian Center: Outcome of
the rst 441 started cycles. Fertil Steril 2007;87:60-73.
[25] Dehlendorf C, Rodriguez MI, Levy K, Borrero S, Steinauer J.
Disparities in family planning. Am J Obstet Gynecol 2010;202:214-20.
[26] Pennell PB. Antiepileptic drugs during pregnancy: What is
known and which AEDs seem to be safest? Epilepsia 2008;49(Suppl.
9):43-55.
[27] Marchington D, Malik S, Banerjee A, et al. Information for ge-
netic management of mtDNA disease: Sampling pathogenic mtDNA mu-
tants in the human germline and in placenta. J Med Genet;47:257261.
[28] Dulac O, Bast T, Dalla Bernardina B, Gaily E, Neville B.
Infantile spasms: Toward a selective diagnostic and therapeutic approach.
Epilepsia 2010;51:2218-9.
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 325
[29] Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms:
A U.S. consensus report. Epilepsia 2010;51:2175-89.
[30] Zweier M, Gregor A, Zweier C, et al. Mutations in MEF2Cfrom
the 5q143q15 microdeletion syndrome region are a frequent cause of se-
vere mental retardation and diminish MECP2 and CDKL5 expression.
Hum Mutat 2010;31:722-33.
[31] Sherr EH. The ARX story (epilepsy, mental retardation, autism,
and cerebral malformations): One gene leads to many phenotypes. Curr
Opin Pediatr 2003;15:567-71.
[32] Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy:
Mutations and mechanisms. Epilepsia 2010;51:1650-8.
[33] Marini C, Scheffer IE, Nabbout R, et al. SCN1A duplications
and deletions detected in Dravet syndrome: Implications for molecular
diagnosis. Epilepsia 2009;50:1670-8.
[34] HarkinLA, McMahon JM, Iona X, et al. The spectrumof SCN1A-
related infantile epileptic encephalopathies. Brain 2007;130:843-52.
[35] Miller IO, Sotero de Menezes MA. SCN1A-related seizure disor-
ders [electronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, ed-
itors. GeneReviews [Internet]. Seattle: University of Washington, 1993.
[36] Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum
of early-onset epileptic encephalopathies associated with STXBP1 muta-
tions. Neurology 2010;75:1159-65.
[37] Pong AW, Takeoka M. ARX mutation in females: An under-
recognized cause of epilepsy and developmental delay. Biology of sei-
zure susceptibility in developing brain. Prog Epileptic Disord 2008;6:
65-74.
[38] Leary LD, Wang D, Nordli DR Jr, Engelstad K, De Vivo DC.
Seizure characterization and electroencephalographic features in Glut-1
deciency syndrome. Epilepsia 2003;44:701-7.
[39] Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic
spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deciency).
Brain 2010;133:2148-59.
[40] Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in in-
dividuals with pyridoxine-dependent seizures. Nat Med 2006;12:307-9.
[41] Salbert BA, Pellock JM, Wolf B. Characterization of seizures as-
sociated with biotinidase deciency. Neurology 1993;43:1351-5.
[42] Wolf B, Jensen KP, Barshop B, et al. Biotinidase deciency:
Novel mutations and their biochemical and clinical correlates. HumMutat
2005;25:413.
[43] HamoshA, Scharer G, VanHove J. Glycine encephalopathy[elec-
tronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[44] Finsterer J. Leigh and Leigh-like syndrome in children and
adults. Pediatr Neurol 2008;39:223-35.
[45] Moller LB, Mogensen M, HornN. Molecular diagnosis of Menkes
disease: Genotype-phenotype correlation. Biochimie 2009;91:1273-7.
[46] Tumer Z, Moller LB. Menkes disease. Eur J Hum Genet 2010;
18:511-8.
[47] Rodriguez D, Gauthier F, Bertini E, et al. Infantile Alexander
disease: Spectrum of GFAP mutations and genotype-phenotype correla-
tion. Am J Hum Genet 2001;69:1134-40.
[48] Reiss J. Genetics of molybdenum cofactor deciency. Hum
Genet 2000;106:157-63.
[49] Nyhan WL. Disorders of purine and pyrimidine metabolism.
Mol Genet Metab 2005;86:25-33.
[50] Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin
19 mutations cause female-limited epilepsy and cognitive impairment.
Nat Genet 2008;40:776-81.
[51] Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental re-
tardation limited to females with PCDH19 mutations can present de novo
or in single generation families. J Med Genet 2010;47:211-6.
[52] Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental
retardation limited to females: An under-recognized disorder. Brain 2008;
131:918-27.
[53] Bellini G, Miceli F, Soldovieri MV, et al. Benign familial neona-
tal seizures [electronic book]. In: Pagon RA, Bird TD, Dolan CR,
Stephens K, editors. GeneReviews [Internet]. Seattle: University of Wash-
ington, 1993.
[54] Berkovic SF, Heron SE, Giordano L, et al. Benign familial
neonatal-infantile seizures: Characterization of a new sodium channelop-
athy. Ann Neurol 2004;55:550-7.
[55] Nasrallah F, Feki M, Kaabachi N. Creatine and creatine de-
ciency syndromes: Biochemical and clinical aspects. Pediatr Neurol
2010;42:163-71.
[56] Marini C, Guerrini R. The role of the nicotinic acetylcholine re-
ceptors in sleep-related epilepsy. Biochem Pharmacol 2007;74:1308-14.
[57] Milone M, Massie R. Polymerase gamma 1 mutations: Clinical
correlations. Neurologist 2010;16:84-91.
[58] Kollberg G, Moslemi AR, Darin N, et al. POLG1 mutations as-
sociated with progressive encephalopathy in childhood. J Neuropathol
Exp Neurol 2006;65:758-68.
[59] Kalachikov S, Evgrafov O, Ross B, et al. Mutations in LGI1
cause autosomal-dominant partial epilepsy with auditory features. Nat
Genet 2002;30:335-41.
[60] Ottman R, Winawer MR, Kalachikov S, et al. LGI1 mutations in
autosomal dominant partial epilepsy with auditory features. Neurology
2004;62:1120-6.
[61] Ottman R. Autosomal dominant partial epilepsy with auditory
features. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[62] Scheffer IE, Berkovic SF. Generalized epilepsy with febrile sei-
zures plus: A genetic disorder with heterogeneous clinical phenotypes.
Brain 1997;120:479-90.
[63] Ramachandran N, Girard JM, Turnbull J, Minassian BA. The
autosomal recessively inherited progressive myoclonus epilepsies and
their genes. Epilepsia 2009;50(Suppl. 5):29-36.
[64] ChinneryPF. Mitochondrial disorders overview[electronic book].
In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews
[Internet]. Seattle: University of Washington, 1993.
[65] Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS
with recurrent complex partial seizures, nonconvulsive status epilepticus,
psychosis, and behavioral disturbances: Case analysis with literature
review. Epilepsy Behav 2010;18:494-7.
[66] DiMauro S, DiMauroS. MERRF[electronic book]. In: Pagon RA,
Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle:
University of Washington, 1993.
[67] Genton P. Unverricht-Lundborg disease (EPM1). Epilepsia
2010;51(Suppl. 1):37-9.
[68] Jansen AC, Andermann E. Progressive myoclonus epilepsy,
Lafora type. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[69] Singh R, Gardner RJ, Crossland KM, Scheffer IE, Berkovic SF.
Chromosomal abnormalities and epilepsy: A review for clinicians and
gene hunters. Epilepsia 2002;43:127-40.
[70] Christodoulou J, Ho G. MECP2-related disorders [electronic
book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[71] Glaze DG, Percy AK, Skinner S, et al. Epilepsy and the natural
history of Rett syndrome. Neurology 2010;74:909-12.
[72] Castren M, Gaily E, Tengstrom C, Lahdetie J, Archer H, Ala-
Mello S. Epilepsy caused by CDKL5 mutations. Eur J Paediatr Neurol
2011;15:65-9.
[73] Pintaudi M, Calevo MG, Vignoli A, et al. Epilepsy in Rett syn-
drome: Clinical and genetic features. Epilepsy Behav 2010;19:296-300.
[74] Williams CA, Dagli AI, Driscoll DJ. Angelman syndrome [elec-
tronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[75] CassidySB, Schwartz S. Prader-Willi syndrome [electronic book].
In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews
[Internet]. Seattle: University of Washington, 1993.
[76] BattagliaA, CareyJC, South ST, Wright TJ. Wolf-Hirschhornsyn-
drome [electronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K,
editors. GeneReviews [Internet]. Seattle: University of Washington, 1993.
[77] Shapira SK, McCaskill C, Northrup H, et al. Chromosome 1p36
deletions: The clinical phenotype and molecular characterization of a com-
mon newly delineated syndrome. Am J Hum Genet 1997;61:642-50.
326 PEDIATRIC NEUROLOGY Vol. 44 No. 5
[78] Yamadera H, Kobayashi K, Sugai K, Suda H, Kaneko S. Astudy
of ring 20 chromosome karyotype with epilepsy. Psychiatry Clin Neurosci
1998;52:63-8.
[79] Bingham PM, Spinner NB, Sovinsky L, Zackai EH, Chance PF.
Infantile spasms associated with proximal duplication of chromosome
15q. Pediatr Neurol 1996;15:163-5.
[80] Battaglia A. The inv dup (15) or idic (15) syndrome (tetrasomy
15q). Orphanet J Rare Dis 2008;3:30.
[81] Shibuya Y, Tonoki H, Kajii N, Niikawa N. Identication of
a marker chromosome as inv dup(15) by molecular analysis. Clin Genet
1991;40:233-6.
[82] Northrup H, Au KS. Tuberous sclerosis complex [electronic
book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[83] Jentarra G, Snyder SL, Narayanan V. Genetic aspects of neuro-
cutaneous disorders. Semin Pediatr Neurol 2006;13:43-7.
[84] Friedman JM. Neurobromatosis 1 [electronic book]. In:
Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Inter-
net]. Seattle: University of Washington, 1993.
[85] Wimmer K, Yao S, Claes K, et al. Spectrumof single- and multi-
exon NF1 copy number changes in a cohort of 1,100 unselected NF1 pa-
tients. Genes Chromosomes Cancer 2006;45:265-76.
[86] Dobyns WB, Das S. LIS1-associatedlissencephaly/subcortical band
heterotopia [electronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K,
editors. GeneReviews [Internet]. Seattle: University of Washington, 1993.
[87] Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P.
Neuronal migration disorders: Clinical, neuroradiologic and genetics as-
pects. Acta Paediatr 2009;98:421-33.
[88] Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker
lissencephaly gene containing G protein beta-subunit-like repeats. Nature
1993;364:717-21.
[89] Dobyns WB, Das S. LIS1-associated lissencephaly/subcortical
band heterotopia. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[90] Sossey-Alaoui K, Hartung AJ, Guerrini R, et al. Human double-
cortin (DCX) and the homologous gene in mouse encode a putative
Ca
2+
-dependent signaling protein which is mutated in human X-linked
neuronal migration defects. Hum Mol Genet 1998;7:1327-32.
[91] Kitamura K, Yanazawa M, Sugiyama N, et al. Mutation of ARX
causes abnormal development of forebrain and testes in mice and X-linked
lissencephalywithabnormal genitalia inhumans. Nat Genet 2002;32:359-69.
[92] Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lis-
sencephaly with cerebellar hypoplasia is associated with human RELN
mutations. Nat Genet 2000;26:93-6.
[93] Matsumoto N, Leventer RJ, Kuc JA, et al. Mutation analysis of
the DCX gene and genotype/phenotype correlation in subcortical band
heterotopia. Eur J Hum Genet 2001;9:5-12.
[94] Gleeson JG, Luo RF, Grant PE, et al. Genetic and neuroradiolog-
ical heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265-9.
[95] Sheen VL, Ganesh VS, Topcu M, et al. Mutations in ARFGEF2
implicate vesicle trafcking in neural progenitor proliferation and migra-
tion in the human cerebral cortex. Nat Genet 2004;36:69-76.
[96] Chang B, Walsh CA, Apse K, Bodell A. Polymicrogyria overview
[electronic book]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
GeneReviews [Internet]. Seattle: University of Washington, 1993.
[97] GropmanAL, Barkovich AJ, Vezina LG, Conry JA, Dubovsky EC,
Packer RJ. Pediatric congenital bilateral perisylvian syndrome: Clinical and
MRI features in 12 patients. Neuropediatrics 1997;28:198-203.
[98] Guerreiro MM, Andermann E, Guerrini R, et al. Familial peri-
sylvian polymicrogyria: A new familial syndrome of cortical maldevelop-
ment. Ann Neurol 2000;48:39-48.
[99] Villard L, Nguyen K, Cardoso C, et al. Alocus for bilateral peri-
sylvian polymicrogyria maps to Xq28. Am J Hum Genet 2002;70:1003-8.
[100] Roll P, Rudolf G, Pereira S, et al. SRPX2 mutations in disorders
of language cortex and cognition. Hum Mol Genet 2006;15:1195-207.
[101] Piao X, Hill RS, Bodell A, et al. Gprotein-coupled receptor-de-
pendent development of human frontal cortex. Science 2004;303:2033-6.
[102] Tsuji S. DRPLA [electronic book]. In: Pagon RA, Bird TD,
Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle: University
of Washington, 1993.
[103] Kasahata N, Iwasaki Y. Dentatorubropallidoluysian atrophy
without involuntary movement or dementiaA case report. Clin Neurol
Neurosurg 2010;112:722-5.
[104] Fluharty AL. Arylsulfatase A deciency [electronic book]. In:
Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Inter-
net]. Seattle: University of Washington, 1993.
Appendix: Glossary
Exon array is a multiplex technology consisting of thou-
sands of DNA oligonucleotide probes, designed to detect
individual exons in one gene or multiple genes.
Fluorescence in situ hybridization is a cytogenetic tech-
nique used to detect and localize the presence or absence of
specic DNA sequences on chromosomes. Fluorescence in
situ hybridization uses uorescent probes that bind only to
those parts of the chromosome with which they exhibit
a high degree of sequence similarity.
Germline mosaicismor gonadal mosaicismis a condition
in which the precursor (germline) cells to the ova and sper-
matozoa are a mixture of two or more genetically different
cell lines.
Haploinsufciency occurs when a diploid organism has
only a single functional copy of a gene (with the other copy
inactivated by mutation), and the single functional copy of
thegene does not produce enoughof a gene product (typically
a protein) to bring about a wild-type condition, leading to an
abnormal or diseased state. Haploinsufciency is responsible
for some but not all autosomal dominant disorders.
Multiplex ligation-dependent probe amplication is
a variation of the polymerase chain reaction that permits
multiple targets to be amplied with only a single primer
pair [1]. Each probe consists of a two oligonucleotides
that recognize adjacent target sites on the DNA. One probe
oligonucleotide contains the sequence recognized by the
forward primer, and the other contains the sequence recog-
nized by the reverse primer.
Polymerase chain reaction amplication is a technique
to amplify a single copy or a few copies of a piece of
DNA across several orders of magnitude, generating
thousands to millions of copies of a particular DNA
sequence.
Preimplantation genetic diagnosis refers to procedures
that are performed on embryos before implantation, and
sometimes even on oocytes before fertilization. Preimplan-
tation genetic diagnosis is considered another method of
prenatal diagnosis. It has the main advantage of avoiding
selective pregnancy termination, because the method es-
tablishes with high probability whether the baby will be
free of the disease under consideration. Preimplantation
genetic diagnosis is thus an adjunct to assisted reproductive
technology, and requires in vitro fertilization to obtain
oocytes or embryos for evaluation.
Pong et al: Molecular Genetic Diagnostics Updates in Epilepsy 327