Elsevier

Epilepsy & Behavior

Volume 37, August 2014, Pages 241-248
Epilepsy & Behavior

Clinical utility of genetic testing in pediatric drug-resistant epilepsy: A pilot study

https://doi.org/10.1016/j.yebeh.2014.06.018Get rights and content

Highlights

  • We retrospectively reviewed the yield and usefulness of genetic testing.

  • Tests: karyotype, microarray, single gene, gene panel, and whole exome sequencing

  • We found a high diagnostic yield: overall — 34.5% and highest for gene panels — 46.2%.

  • Results were often not predictable from phenotypes with often therapeutic implications.

Abstract

Rationale

The utility of genetic testing in pediatric drug-resistant epilepsy (PDRE), its yield in “real life” clinical practice, and the practical implications of such testing are yet to be determined.

Goal

To start to address the above gaps in our knowledge as they apply to a patient population seen in a tertiary care center.

Methods

We retrospectively reviewed our experience with the use of clinically available genetic tests in the diagnosis and management of PDRE in one clinic over one year. Genetic testing included, depending on clinical judgment, one or more of the following: karyotype, chromosomal microarray, single gene sequencing, gene sequencing panels, and/or whole exome sequencing (WES).

Results

We were more likely to perform genetic testing in patients with developmental delay, epileptic encephalopathy, and generalized epilepsy. In our unique population, the yield of specific genetic diagnosis was relatively high: karyotype 14.3%, microarray 16.7%, targeted single gene sequencing 15.4%, gene panels 46.2%, and WES 16.7%. Overall yield of diagnosis from at least one of the above tests was 34.5%. Disease-causing mutations that were not clinically suspected based on the patients' phenotypes and representing novel phenotypes were found in 6.9% (2/29), with an additional 17.2% (5/29) demonstrating pharmacologic variants. Three patients were incidentally found to be carriers of recessive neurologic diseases (10.3%). Variants of unknown significance (VUSs) were identified in 34.5% (10/29).

Conclusions

We conclude that genetic testing had at least some utility in our patient population of PDRE, that future similar larger studies in various populations are warranted, and that clinics offering such tests must be prepared to address the complicated questions raised by the results of such testing.

Introduction

Advancing technology in the areas of genetics and genomics has opened new avenues for diagnosis and understanding human disease. Tests that were previously solely the purview of research are now available commercially and, in some cases, direct-to-consumer [1]. Genetic testing can allow specific diagnoses and may influence therapy selection. For example, patients with sodium channel mutations such as in Dravet syndrome should generally avoid carbamazepine and lamotrigine [2], and genetic polymorphisms can predict the profile of drug metabolism and propensity for severe allergic reactions [3].

Identifying a specific genetic diagnosis can prevent further unnecessary and invasive diagnostic testing as well as allow genetic counseling for family members. But some clinicians argue that many of these clinical decisions can be arrived at through clinical data without expensive and confusing genetic investigations [4]. It has been recommended that genetic testing in epilepsy should be used in only select cases [5]. However, specific guidelines for when to apply genetic testing, the cost effectiveness of various testing modalities, and the clinical and practical implications of such studies are not available [6], [7].

To start to address these questions, we reviewed in this study our experience with clinically available genetic studies and the implications of such testing on the diagnosis and management of pediatric drug-resistant epilepsy (PDRE) in our tertiary care center. Our goal was to describe, in retrospect, the yield of a variety of genetic testing modalities applied to our select referral population of patients.

Section snippets

Methods

In this retrospective chart review study, patients with PDRE were identified by reviewing records of all consecutive new patients seen in one pediatric epilepsy clinic during a 12-month period. Established patients who underwent whole exome sequencing (WES) during the study period were also included in the data collection (see Inclusion criteria below). The protocol was approved by the Duke IRB before starting the study.

Patient characteristics (Fig. 1, Table 1)

During the 12-month study period, 175 new patients were seen in one epilepsy clinic (Fig. 1). These included 37 patients (19 boys) with DRE. Of these 37, 25 underwent genetic testing. Of the remaining 144 patients, 47 had nonepileptic events such as syncope, psychogenic nonepileptic seizures, or other behavioral spells, and 91 patients had epileptic events that either did not further recur, were responsive to medical therapy, or were indeterminate (seizure freedom was less than 3 times their

Patient characteristics

Our pilot data presented in this study are based on patients referred to our pediatric epilepsy clinic in a tertiary care center. Our cohort is likely not to be representative of patient populations at many other centers. However, there are similarities of our patients to previous reports of pediatric epilepsy populations. Pediatric drug-resistant epilepsy accounts for 9–24% of cases of pediatric epilepsy and represents a significant portion of the disease burden of pediatric epilepsy [30]. The

Disclosure

Neither of the two authors has a conflict of interest.

Acknowledgments

We thank the staff of the Duke Pediatric Epilepsy Clinic and of the Division of Pediatric Neurology, and our colleagues and staff in Genetics, Clinical Neurophysiology and Laboratory Medicine. Special thanks to Karen Cornett, Tara McKellar, and Blythe Devlin for their invaluable assistance in the regulatory issues and planning of this study.

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    Current address: Nationwide Children's Hospital, Columbus, OH, USA.

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