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Molecular Case Studies | REVIEW

Genomic testing in pediatric epilepsy

Drew M. Thodeson1 and Jason Y. Park2,3
1
Department of Pediatrics, 2Department of Pathology, 3Eugene McDermott Center for Human Growth
and Development, UT Southwestern Medical Center, Dallas, Texas 75235, USA

Abstract Genomic testing has become routine in the diagnosis and management of pedi-
atric patients with epilepsy. In a single test, hundreds to thousands of genes are examined
for DNA changes that may not only explain the etiology of the patient’s condition but may
also inform management and seizure control. Clinical genomic testing has been in clinical
practice for less than a decade, and because of this short period of time, the appropriate
clinical use and interpretation of genomic testing is still evolving. Compared to the previ-
ous era of single-gene testing in epilepsy, which yielded a diagnosis in <5% of cases,
many clinical genomic studies of epilepsy have demonstrated a clinically significant diag-
nosis in 30% or more of patients tested. This review will examine key studies of the past
decade and indicate the clinical scenarios in which genomic testing should be considered
standard of care.

INTRODUCTION

Epilepsy occurs at a frequency of four to eight individuals per 1000 in the United States
(Helmers et al. 2015; Gupta et al. 2016). Overall health-care costs for patients with epilepsy
are proportional to the number of epileptic episodes with a threefold higher cost in patients
with one or more seizures per week compared to individuals with less than one seizure per
year (Gupta et al. 2016). Our knowledge of the various causes of epilepsy is still mostly un-
known with approximately six out of 10 patients with unknown etiology (Hauser and
Kurland 1975; Hauser et al. 1996). Frequently, there is a diagnostic odyssey undertaken
to find the etiology including neurodiagnostics, neuroimaging, and metabolic and genetic
testing.
With the advent of clinical genomic testing 10 years ago, physicians were empowered to
Corresponding author: progress from sequencing single genes in serial to sequencing hundreds to thousands of
jaspar@[Link] genes in parallel (Evans et al. 2017). Indeed, genomic tests are not single tests but rather
an aggregate of millions of tests comprised of individual nucleotide positions. The quick
© 2019 Thodeson and Park This adoption of clinical genomic testing was accomplished because defects in many different
article is distributed under the genes result in the same clinical presentation; similarly, a single defective gene can exhibit
terms of the Creative Commons many different phenotypes (Novotny 2017). The prior paradigm of sequentially testing indi-
Attribution-NonCommercial
License, which permits reuse and
vidual genes has a low diagnostic yield and infrequently provides a genetic explanation for a
redistribution, except for clinical diagnosis. Single-gene testing is a time-consuming and expensive process that is no
commercial purposes, provided longer practical in the evaluation of patients with epilepsy (Wang et al. 2014). The capability
that the original author and to rapidly investigate multiple genes in parallel has solved diagnostic odysseys for many pa-
source are credited.
tients and families (Mroch et al. 2012). Still, it is unclear to most clinicians when to order ge-
nomic testing. The most recent guideline endorsed by the International League Against
Published by Cold Spring Harbor
Epilepsy was published in 2010 and concludes, “… because the field is moving rapidly,
Laboratory Press
with new information emerging practically every day, we present a framework for consider-
doi:10.1101/mcs.a004135 ing the clinical utility of genetic testing that can be applied to many different syndromes and

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Molecular Case Studies Genomic testing in pediatric epilepsy

clinical contexts. Given the current state of knowledge, genetic testing has high clinical utility
in few clinical contexts, but in some of these it carries implications for daily clinical practice”
(Ottman et al. 2010).
In this review, we will discuss the most commonly used genomic tests in clinical practice
as it relates to epilepsy. We will also discuss the limitations to and pitfalls of genomic testing.
Finally, we will discuss the potential cost-effectiveness of integrating genomic testing into
routine clinical practice and present an operational approach for utilizing genomic testing.

TYPES OF GENOMIC TESTING

Microarray
Since the early 2000s, chromosomal microarray analysis (CMA) has been available for ge-
nome-wide analysis. CMA techniques use nucleic acid probes to detect copy-number
changes (gains and deletions) across the genome. When these copy-number changes occur
in regions with genes, the loss or gain in gene function may be predicted. In one pediatric
epilepsy study, 226 pediatric patients with first-time epilepsy were examined by CMA
(Vlaskamp et al. 2017). A clinically relevant copy-number variant was detected in 11% of pa-
tients (n = 24). The variants detected had a wide range in size from 88 kb to 21.1 Mbp. In an-
other pediatric epilepsy study, 805 patients underwent CMA explaining 5% of cases (n = 40);
the variants in this study ranged in size from 18 kb to 142 Mbp (Olson et al. 2014). In one of
the largest studies (n = 1255) of patients with epilepsy, 10.9% of patients had a pathogenic
variant, and an additional 1.7% of patients had a copy-number variant that was deemed to be
possibly pathogenic (Coppola et al. 2019). With a diagnostic yield of 5%–13%, CMA is a use-
ful and sometimes critical test in the genetic diagnosis of epilepsy.
The copy-number information from microarrays can now be derived from some genomic
DNA sequencing tests; thus, a single DNA test can identify both single-nucleotide variants
and larger deletions of exons or whole genes. In a large study of 2603 patients with hetero-
geneous clinical presentations, reanalysis of exome data for copy-number variations identi-
fied a variant relevant to the patient’s phenotype in 4.7% (n = 123) of cases; the variant sizes
ranged from 727 bp to 15.3 Mbp. In a recent study focused on epilepsy, 168 families with
epilepsy with negative test results from exome sequencing were reanalyzed using software
designed to detect copy-number variation (Tsuchida et al. 2018). The exome data from these
families was reanalyzed using software designed to detect copy-number variation.
Pathogenic copy-number variants were detected in 10.7% of patients examined (n = 18).
Compared to traditional CMA, the exome-derived data yielded a much wider range in
size from 260 bp to 45.7 Mbp. This study suggests that existing patient data may have ex-
panded utility with the development of new software algorithms. Genome-wide copy-num-
ber variation by CMA is still cost-effective to use for clinical diagnosis; however, in the near
future, clinical laboratories will likely perform a single next-generation sequencing (NGS) test
that assesses both single-nucleotide variation and copy-number variation.

Gene Panel
In children with epilepsy of early onset or without specific dysmorphic features, targeted
NGS panels are the most cost-effective initial test after electroencephalogram and neuroim-
aging. Diagnostic yield is variable depending on the population sampled. In one of the larg-
est surveys of diagnostic yield, a summary of the clinical experience of a reference lab
(GeneDx) examined the diagnostic yield of 8565 patients tested by gene panel (17, 18,
50, 53, and 70 genes in each panel) and exon-level microarray (December 2011 to
December 2015) (Lindy et al. 2018). Overall, a 15.4% diagnostic yield was achieved in this

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heterogeneous population (average age, 5 yr 8 mo; range, 1 wk to 47 yr). The study not only
identified the most commonly observed genes (MECP2, KCNQ2, SCN1A, SCN2A, STXBP1,
and PRRT2), but also identified some genes that were only impacted by de novo variants
(CDKL5, STXBP1, SCN8A, GABRA1, and FOXG1).
Studies on more defined populations have shown higher diagnostic yield from genomic
testing. In a study of 74 pediatric patients with intractable early-onset epilepsy, a NGS panel
of 172 genes demonstrated a 37.8% diagnostic yield (Rim et al. 2018). The patients in this
study had a 7.5 mo mean age of epilepsy; the majority of patients (85.1%) had epilepsy onset
within the first year of life. The 37.8% diagnostic yield (n = 28) was attributed to 17 different
genes, with the most frequently affected gene implicated in three cases (STXBP1). A sepa-
rate study using a 46-gene NGS panel testing 216 patients with epilepsies ranging from neo-
natal seizures to epileptic encephalopathies (Møller et al. 2016). A disease-causing variant
was identified in 23% (n = 49) of patients. The cohort consisted of both pediatric and adult
patients with 23% of >18 yr of age. Of the 46 genes tested, 19 had disease-causing variants.
Additionally, genes with disease-causing variants were sometimes implicated in more than
one patient. The most frequently implicated gene was SCN1A (n = 12). The other genes
that were implicated in more than one patient were CDKL5 (n = 4), GABRA1 (n = 2),
GABRB3 (n = 2), KCNQ2 (n = 4), SCN2A (n = 6), SCN8A (n = 3), SLC2A1 (n = 3), and
STXBP1 (n = 4). Nine additional genes were each implicated only once each. Neonatal-onset
epilepsies (57%) followed by epileptic encephalopathies (32%) were most frequently diag-
nostic. Interestingly, in this study only 3% of cases reported had a variant of uncertain signifi-
cance (VUS), whereas other studies have identified a VUS in >30% of cases (Lindy et al. 2018;
SoRelle et al. 2018). This large difference in VUS detection rate probably can be attributed to
differences in variant interpretation criteria; the use of recently published standardized inter-
pretation guidelines (Richards et al. 2015) shows a high rate of VUS detection in epilepsy
panel studies (SoRelle et al. 2018).

Exome
In theory, exome studies are comprehensive tests that examine all DNA variants that encode
protein. However, in the context of epilepsy, exome studies have overlapping diagnostic
yield with gene panels (Wang et al. 2014). A more recent exome study of epileptic enceph-
alopathies identified de novo variants in 59% of patients (Heyne et al. 2018). Patients may
have unique disease-causing variants that are not present in other family members. In theory,
exome testing provides an unbiased approach for investigating rare genetic etiologies. In
practice, when selecting clinical exome studies, the limited increase in diagnostic yield
over gene panels should be recognized.
A large clinical exome study for patients with epilepsy examined 1131 patients: 314
had seizures and 817 were without seizures (Helbig et al. 2016). Both adult and pediatric pa-
tients were participants with the majority of patients examined by trio (proband plus biologic
parents) analysis (80.9%). The remainder were a combination of proband only or proband
plus one first-degree relative. The diagnostic yield of clinical exome was 33.4% for epilepsy
patients (105 of 314). In comparison, the nonepilepsy group had a diagnostic yield of 25.9%
(212 of 817). A total of 93 genes were implicated: 21 were found in two or more patients; six
genes were seen in three or more patients (KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and
STXBP1). Of the patients tested, 80% previously had negative testing by microarray or tar-
geted gene panels. This study was by a reference laboratory, and the authors recognized
that the findings in the patients referred to their laboratory may not be generalizable to all
patients with epilepsy.
Another approach to exome sequencing is to analytically sequence all coding genes, but
only examine and interpret a subset of genes that were related to the patient’s epilepsy type

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(Perucca et al. 2017). In 40 consecutive pediatric and adult patients with focal epilepsy, 64
epilepsy-associated genes were analyzed. In this study 12.5% (5 of 40 patients) had a
disease-associated variant; one patient each for a defect in SCN1A, DEPDC5, PCDH19,
GABRG2, or NPRL2. The median age of seizure onset of patients with an identified variant
was 18 mo (range 8 mo to 18 yr) versus 18 yr (range 18 mo to 70 yr) for patients without
an identified variant. This study identified a correlation between age of epilepsy onset
and the diagnostic yield; patients with onset of epilepsy before the age of 2 yr were more
likely to have positive genetic findings.
Building on this concept, a prospective study has focused on the use of genetic testing in
children with epilepsy onset at <3 yr of age (Berg et al. 2017). This multi-institutional study
enrolled 775 patients with a median age of onset of 7.5 mo. A subset of 327 patients under-
went genetic testing, and 40.4% received a genetic diagnosis. The study included karyo-
type, microarrays, epilepsy gene panels, exomes, and mitochondrial panels and other
tests. The highest yield test in this study was karyotype (26 of 59, 44.1%), followed by exome
(11 of 33, 33.3%), 31 of 114 epilepsy panels (27.2%), mitochondrial panels (4 of 20, 20%), and
microarrays 32 of 188 (17%). The authors concluded that genetic investigation should be part
of the initial evaluation of early-onset epilepsy, and testing should be individualized based
on the clinical presentation.
A parallel comparison of exome versus conventional genetic testing in 150 pediatric pa-
tients with complex neurologic disorders used both conventional diagnostic workup (imag-
ing, biopsies, lumbar punctures, and sequential gene-specific testing) and exome
sequencing (trio) (Vissers et al. 2017). The majority of patients (n = 143) did not have a family
history of neurologic disorders. The most frequent clinical findings in the patients were intel-
lectual disability (n = 78), movement disorders (n = 20), and neuromuscular disease (n = 8).
The patients examined by exome sequencing alone had a higher diagnostic yield of
29.3% compared to the conventional diagnostic workup’s yield of 7.3%. The conventional
diagnostic workup with sequential single gene sequencing had an average of 4.6 genetic
tests performed before reaching a diagnosis. The study also examined diagnostic concor-
dance between exome and conventional workup. Eight patients reached the same diagnosis
by either method. Thirty-six patients only had a diagnosis by exome, and three patients only
had their diagnosis through conventional diagnostic workup with sequential gene testing.
The three patients with a genetic diagnosis missed by exome included a patient with 9-bp
duplication event, a repeat expansion in FMR1, and a mosaic 27-Mbp duplication of
Chromosome 7. This study is unique because it examines the role of exome testing in com-
parison to conventional diagnostic modalities. Future studies on exome or other advanced
genomic technologies should utilize this design of direct comparison with conventional di-
agnostic modalities.

TECHNICAL LIMITATIONS AND PITFALLS

An important concept to consider when selecting any genomic test is that there is only a
subset of genes that is clinically useful to analyze. Of the greater than 18,000 genes that
encode protein, less than 6000 currently have specific associations with human disease.
Although both coding and noncoding variants are identified, the clinical analysis is limit-
ed to variants near or in genes with known association with human disease. To put this
into perspective, of the three billion bases examined in whole-genome testing, <1% of
the data is currently useful for clinical diagnosis. Indeed, the technology for sequencing
DNA has advanced to the point that the ability to test DNA outpaces the ability to ability
to deliver affordable and clinically meaningful interpretations that are relevant to the pa-
tient’s care.

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Other limitations of genomic tests include incidental findings, nonpaternity, and analyt-
ical failures. Genomic tests may uncover incidental (secondary) findings of significant conse-
quence to the future health and unrelated to the patient’s current health (Green et al. 2013;
Kalia et al. 2017). Incidental findings are estimated to be in 1%–3% of the U.S. population
and include adult-onset diseases such as cancer, cardiac abnormalities, or neurodegenera-
tive disease (Dorschner et al. 2013). In addition to genetic findings unrelated to the patient’s
current health, genetic tests may reveal nonpaternity. Nonpaternity varies widely depending
in studies with a median rate of 3.7% (range 0.8% to 30%) (Bellis et al. 2005). Limitations of
incidental findings and nonpaternity can be mitigated by careful pretest counseling of the
patient and/or family.
Analytical inconsistencies or failures are a sign of the relative newness of the technol-
ogy. The quality metrics for standardization of testing is still in flux. Specifically, for epilep-
sy testing, the content (genes examined) has been in constant evolution. New genetic
discoveries may increase the number of relevant genes to be tested. Thus, there may
be variation in the exact genes examined by different laboratories. Alternatively, a labora-
tory may provide testing by using an exome kit; however, laboratories may analyze all
genes in the exome or only examine a small subset of genes that they deem to be clinically
relevant.
Analytical quality metrics are also evolving in terms of how “deeply” genomic tests se-
quence a target. Each nucleotide position needs 40 reads per nucleotide position (40×) to
achieve a 95% confidence of a heterozygous change (Meynert et al. 2013, 2014). The com-
monly used target for minimum reads of data is 20 (20×); however, this is predicted to miss
5%–15% of heterozygous variants, which could be a critical error in rare disease detection
(Meynert et al. 2013). In studies of both exome (Park et al. 2015) and whole-genome
(Dewey et al. 2014) sequencing, small inadequacies in coding nucleotide coverage can
lead to clinically significant deficiencies in analysis of important genes.
Another quality consideration is confirmation by Sanger sequencing. The quality of NGS
is improving and some have suggested that Sanger confirmation is no longer necessary
(Beck et al. 2016). However, other studies have shown that although NGS quality is quite
high (>90% of variants identified), there are specific analytical scenarios in which Sanger con-
firmation is necessary (Strom et al. 2014; Baudhuin et al. 2015). From the perspective of clin-
ical providers and patients, there should be a preference for laboratories that either perform
Sanger confirmation of all clinically important variants or otherwise have established criteria
for when Sanger confirmation is necessary.
A future consideration for genomic testing is the need for longitudinal reinterpretations.
For example, a patient presenting with intractable epilepsy at 2 yr of age may have a geno-
mic test performed and VUSs with or without clinical significance may be identified. Any var-
iants that are identified are interpreted at the time of the testing, but these variants can also
be reinterpreted with the passage of time and the development of the medical literature.
Periodic reanalysis of existing genetic data is not performed by all clinical laboratories.
However, studies have shown that genetic diagnoses may significantly change over time
(Costain et al. 2018; Hiatt et al. 2018; Mersch et al. 2018; SoRelle et al. 2018). The types
of diagnostic changes include not only upgrades from uncertain diagnosis to disease-caus-
ative diagnosis, but also can include downgrades from pathogenic diagnoses to benign find-
ings. The physicians who use genomic tests must communicate with their patients that the
interpretation of genetic variants may change with advances in medical knowledge.
Furthermore, as pediatric patients reach majority status and seek information on the risk of
future-onset diseases (e.g., neurodegenerative, cancer), then an exome data set should
be made available for further reanalysis for adult-onset disorders. Clinical care providers
who order genomic testing on their patients should be familiar with a basic checklist of qual-
ity considerations for clinical genomic laboratories (Table 1).

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Table 1. Quality checklist in clinical laboratory and test selection

Accreditation—Quality programs (accreditation) and certifications for the laboratory. In the United States,
CLIA is the most basic type of clinical laboratory certification. The College of American Pathologists
(CAP) provides specific accreditation requirements and on-site inspections for genomic laboratories.
Some states such as New York have specific requirements for genomic testing.
Genes tested—For a panel, the exact genes tested should be provided. For exome, the laboratory
should be able to provide information on which genes are completely tested (e.g., 100% of coding
nucleotides at ≥20× at all nucleotide positions) or partially tested.
Sanger confirmation—Sanger confirmation of genomic test results. The laboratory should provide criteria
for when Sanger confirmation is performed.
Variant reinterpretation—How does the laboratory update providers and patients of changes in the
classification of clinical significance of variants?

TREATMENT IMPLICATIONS

Although genomic testing is predominantly diagnostic, there are treatment implications in

some cases. In a retrospective review of 50 patients with exome testing, 48% had a genetic
diagnosis; the majority of management changes from those diagnoses were prognostic or
informative for family planning (Nolan and Carlson 2016). However, there were five genes
in patients that involved medication changes: CACNA1A (acetazolamide); NSD1 (discontin-
ued mitochondrial cocktail); SCN1A (avoid carbamazepine, lamotrigine, or vigabatrin);
SLC13A5 (citrate transport defect; acetazolamide improved some symptoms); and WDR45
(associated sleep concerns; started clonidine). In another series, a patient was discovered
to have compound heterozygosity of pathogenic variants in PNPO (pyridoxamine
5-prime-phosphate oxidase) and was placed on oral vitamin therapy (Fung et al. 2017).
Importantly, although the patient was seizure-free on a combination of pyridoxal 5-phos-
phate and valproate, his preexisting severe developmental delays and visual deficits did
not improve. Beyond vitamin-responsive epilepsies, NGS panels are helpful in identifying
other diagnoses that have emerging evidence for precision medicine including GLUT-1
spectrum disorders, certain sodium and potassium channelopathies, and other rare inborn
errors of metabolism (e.g., cerebral creatine deficiency syndromes) (Table 2; Dang and
Silverstein 2017).

COST-EFFECTIVENESS

In Canada, a cost study model, CAUSES (clinical assessment of the utility of sequencing and
evaluation for service) examined service delivery models of singleton (proband only) exome
and trio exome sequencing (Dragojlovic et al. 2018). The goal of the model is to provide
expert consultation in suspected monogenic disorders in British Columbia in efforts to
define clinical utility of exome and genome sequencing. The clinical delivery service model
in CAUSES includes clinical consultation with a committee of genetics specialists, test facil-
itation in a contract research laboratory, and analysis of the research laboratory data by the
CAUSES team. Any clinically significant variants were confirmed by Sanger sequencing in a
hospital-based clinical laboratory and subsequently reported in the medical record and dis-
cussed with families. The CAUSES study included analysis of 500 families. In their model
simulation using data from their CAUSES delivery of care, the cost assessment (including
all clinical services) was $6437 versus $2576 for trio and singleton, respectively.
Importantly, this study modeled a cost per positive diagnosis and estimated that the cost
per positive diagnosis was $19,340 and $10,700 for trio and singleton, respectively. This

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Table 2. Genes and syndromes with therapeutic implications

Gene Syndrome(s) Therapeutic implication

ALDH7A1 Epilepsy, pyridoxine-dependent Pyridoxine (Yang et al. 2014)

CACNA1A Calcium channelopathy associated with ataxia Acetazolamide (Spacey 1993; Nolan and Carlson 2016)
CHRNA2 Autosomal dominant nocturnal frontal lobe epilepsy Nicotine (Fox et al. 2018)
CHRNA4 Autosomal dominant nocturnal frontal lobe epilepsy Nicotine (Pavlakis and Douglass 2015; Fox et al. 2018;
Oates et al. 2018)
CHRNB2 Epilepsy, nocturnal frontal lobe, 3 Nicotine (Zerem et al. 2013; Sieciechowicz and Kohrman
2015)
EPM2A Epilepsy, progressive myoclonic 2A (Lafora) Avoid sodium channel blockers (lamotrigine and phenytoin)
(Jansen and Andermann 1993)
GRIN2A Epileptic encephalopathy, epileptic-aphasia syndrome (Landau– Memantine (Pierson et al. 2014)
Kleffner syndrome, lectrical status epilepticus during sleep)
KCNQ2 Epileptic encephalopathy, early infantile, 7 Carbamazepine, oxcarbazepine, phenytoin (Pisano et al.
2015; Sands et al. 2016)
KCNQ3 Seizures, benign neonatal, 2 Phenobarbital, carbamazepine (Sands et al. 2016)
KCNT1 Epilepsy, nocturnal frontal lobe, 5 Quinidinea (Mikati et al. 2015)
Epileptic encephalopathy, early infantile, 14
PCDH19 Epileptic encephalopathy, early infantile, 9 Ganaxolone (Farnaes et al. 2018); stiripentol (Trivisano et al.
2015)
PNPO Pyridoxamine 5′ -phosphate oxidase deficiency Pyridoxal-5-phosphate (vitamin B6) (Mills et al. 2014; Guerin
et al. 2015)
POLG Mitochondrial DNA depletion syndromes 4A, 4B Avoid sodium valproate (Stewart et al. 2010)
Mitochondrial recessive ataxia syndrome
Progressive external opthalmoplegias
PRRT2 Convulsions, familial infantile, with paroxysmal choreoathetosis Carbamazepine (Li et al. 2013; Dale et al. 2014)
Episodic kinesigenic dyskinesia 1
Seizures, benign familial infantile, 2
SCN1A Epilepsy, generalized, with febrile seizure plus, type 2 Bromide (Lotte et al. 2012; Shi et al. 2016); stiripentol
Epileptic encephalopathy, early infantile, 6 (Dravet) (Balestrini and Sisodiya 2017); avoid sodium channel
Febrile seizures, familial, 3A blockers (lamotrigine and phenytoin) (Nolan and Carlson
Migraine, familial hemiplegic, 3 2016; Shi et al. 2016)
SCN2A Epileptic encephalopathy, early infantile, 11 High-dose phenytoin (Dilena et al. 2017; Flor-Hirsch et al.
Seizures, benign familial infantile, 3 2018)
SCN8A Epileptic encephalopathy, early infantile, 13 High-dose phenytoin (Barker et al. 2016; Boerma et al.
Seizures, benign familial infantile, 5 2016)
SLC13A5 Epileptic encephalopathy, early infantile, 25 Acetazolamide (Nolan and Carlson 2016); stiripentol
(Alhakeem et al. 2018)
SLC2A1 GLUT1 deficiency syndrome Ketogenic diet, triheptanoin (Pascual et al. 2014; Koch and
Weber 2018)
TSC1 Tuberous sclerosis-1 Vigabatrin, everolimus (Curatolo et al. 2018)
TSC2 Tuberous sclerosis-2 Vigabatrin, everolimus (Curatolo et al. 2018)

Adapted from Dang and Silverstein 2017.

a
Quinidine may be ineffective (Mullen et al. 2018).

is not the first cost analysis study of exome testing, but it is one of the more comprehensive
studies that takes into account not only the cost of the test, but also the cost of each of the
clinical components that associated with the test such as genetic counseling, travel, and oth-
er costs. The authors report that only 4% of the patients in their study had incidental find-
ings; however, the downstream cost of incidental findings reported to patients was not
calculated or modeled.

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In Australia, Tan et al. (2017) examined the utility of singleton exome sequencing in pe-
diatric patients with suspected monogenic disorder who had not had previous genetic test-
ing. Forty-four children were enrolled in this prospective study and the diagnostic yield
within this population was 52%. In their exome analysis only a subset of 3203 genes were
examined. A clinical history of epilepsy was not a specific focus of their study, but many pa-
tients had a CNS phenotype characterized by intellectual disability. Overall, the authors pro-
jected the total health costs (including medical consultations, neurophysiological testing,
diagnostic testing, travel, etc.) of these 44 patients to be >$430,000 ($9772 per patient).
In terms of diagnostic testing, the authors proposed four different diagnostic models: (1)
standard management without exome; (2) standard management with exome; (3) exome
at initial tertiary care appointment; and (4) exome at initial genetics appointment. Within
their model, the lowest cost per diagnosis cost was found with exome sequencing at initial
tertiary care management ($7526 per diagnosis) followed by exome at first genetics visit
($10,225 per diagnosis). Importantly, there was no predicted savings by performing exome
after a standard diagnostic workup, suggesting exome sequencing may be a reasonable
first-line test in suspected pediatric monogenic disorders.
Cost-effectiveness of genomic testing has been examined specifically for patients with
severe epilepsies of infancy (Howell et al. 2018). An incremental cost-effectiveness ratio
was examined for patients with epilepsy diagnosed from 2011 to 2013. Patients were includ-
ed when meeting the criteria of seizure onset before 18 mo of age, frequent seizures, epilep-
tiform EEG, and failure of two or more antiepileptic drugs. As part of routine care, genetic
testing was only performed when MRI and EEG were negative. The genetic testing included
gene sequencing panels (39 to 65 genes), chromosomal analysis, and exome and whole-
genome sequencing. The particular exome analysis in this study was exome sequencing
with analysis and interpretation limited to 341 genes known to be associated with infan-
tile-onset epilepsy. The overall diagnostic yield for genetic testing was 54% (62 of 114).
Cost-effectiveness was then modeled using only the exome data to calculate the cost per
diagnosis if the exome were performed earlier or later in the patient’s care. The baseline
model used no exome testing and had a diagnostic yield of 45% with a total cost of
$661,103 and an average cost per diagnosis $16,951. In contrast when exome was used early
in the patient’s care (after MRI, microarray, routine blood, and urine metabolic tests), a diag-
nostic yield of 53% was achieved with overall lower cost—$445,597 total cost and an average
cost per diagnosis of $9904. The least cost-effective model was using exome as the last
diagnostic modality—$738,136 total cost and an average cost per diagnosis of $15,378.
The investigators concluded that exome testing is clinically important and cost-effective in
evaluation of early-onset intractable epilepsy. Other studies have noted cost savings ranging
from $2000 to $7000 per diagnosis when exome sequencing is considered early in the diag-
nostic pathway (Riechmann et al. 2015; Vissers et al. 2017). A recent meta-analysis identified
the diagnostic yield and cost-effectiveness of CMA, gene panels, and exome for patients
with epilepsy (Sánchez Fernández et al. 2019). In this study, exome had the highest diagnos-
tic yield of 32% (range 22%–44%), followed by gene panels (23%; 18%–29%), and CMA (8%;
6%–12%). Based on these diagnostic yields, the most cost-effective test was gene panel test-
ing with an incremental cost-effectiveness ratio of $15,848 per diagnosis, followed by exome
with $34,500 per diagnosis. The authors identified the most cost-effective strategy as a gene
panel, followed by CMA, then exome. The meta-analysis did not support CMA as a first-tier
diagnostic test for patients with epilepsy.
There is inconsistent insurance coverage of genetic testing in the United States. Indeed,
the evidence used by insurers in the United States for coverage of genetic testing is different
than evidence used for other medical tests such as radiology and drug approval (Chambers
et al. 2017). In a systematic study, five insurance payers were examined for a total of 55 rel-
evant coverage policies relevant to 313 gene panels. Clinical guidelines were cited in 84% of

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Molecular Case Studies Genomic testing in pediatric epilepsy

Figure 1. Clinical pathway for genomic evaluation of pediatric epilepsy. A clinical pathway for genomic man-
agement of pediatric patients with epilepsy begins with a clinical diagnosis of epilepsy by a neurologist. This is
followed by routine EEG and brain MRI. If the patient has a diagnostic MRI and/or EEG, the patient proceeds to
targeted testing and individualized ASM followed by subspecialty referral for further management by epilep-
tologists and/or genetic specialists. If the MRI and/or EEG are not diagnostic, the patient is started on an em-
piric course of ASM. If the patient has either two failures of empiric therapy or one failure of empiric therapy
and an additional risk factor, then the patient has genomic epilepsy testing performed (gene panel vs. exome
[proband-only or trio]). After genomic testing, the patient is then referred to subspecialty consultation with an
epileptologist and/or genetic specialist. ∗ Standard of care testing for children with developmental delay in-
cludes CMA and fragile X (if male). (ASD) Autism spectrum disorder, (ASM) antiseizure medication, (CMA) chro-
mosomal microarray, (EEG) electroencephalogram, (ID) intellectual disability, (MRI) magnetic resonance
imaging.

policies (range 73%–100%). Cost-effectiveness and budget impact studies were rarely cited
by payers (5% of policies with a range of 0%–7%). Individual clinical studies were cited in 69%
of policies (range 50%–87%). The reason for inconsistent coverage is multifactorial, including
evolving techniques and technologies, lack of long-term clinical information on rare genetic
disorders, and difficulty defining the clinical validity and utility of gene panel tests. The in-
consistent financial coverage of genomic testing for patients with epilepsy remains a major
obstacle to clinical implementation in the United States.

CONCLUSIONS

Genomic testing in epilepsy is evolving diagnostically and there are emerging therapeutic
considerations for a number of genetic epilepsy syndromes. However, the literature supports
that a thorough clinical assessment is needed prior to evaluating a patient by a genomic test.

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Previous studies have confirmed that diagnostic yields in certain epilepsy populations lead
to high diagnostic rates and are cost-effective in comparison to conventional diagnostic mo-
dalities and prior methods of serial sequencing of individual genes.
In the current era of clinical medicine, which is characterized by financial pressures and
cost sensitivity, clinical practitioners need to be judicious in cost of their patient manage-
ment. Prior authorization has become a routine step in the process for obtaining genomic
testing for patients. From the perspective of cost mitigation, our clinical practice has imple-
mented a clinical pathway for genomic testing in pediatric epilepsy (Fig. 1). Moreover, there
is mounting evidence that genomic testing in intractable epilepsy with childhood onset may
lead to precision therapies and is becoming standard practice at most tertiary care institu-
Competing Interest Statement tions. Indeed, we stipulate that these genetic testing methods will lead to more streamlined
The authors have declared no diagnostic algorithm and ultimately provide life-changing precision medicine to patients
competing interest. with epilepsy.

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