Elsevier

Epilepsy Research

Volume 131, March 2017, Pages 1-8
Epilepsy Research

Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy

https://doi.org/10.1016/j.eplepsyres.2017.02.001Get rights and content

Highlights

Abstract

Objective

Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The ‘real-world’ clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis.

Methods

We performed WES, followed by targeted analysis of 64 epilepsy genes, on 40 consecutive children and adults enrolled prospectively from routine clinical practice who had MRI-negative focal epilepsy and a family history of febrile seizures or any type of epilepsy in at least one first- or second-degree relative. Exclusion criteria were previous genetic testing, severe intellectual disability and benign focal epilepsies of childhood.

Results

5/40 (12.5%) patients had a pathogenic or likely pathogenic variant, detected in SCN1A, DEPDC5, PCDH19, GABRG2 or NPRL2. Identifying a pathogenic SCN1A variant in a patient with drug-resistant epilepsy prompted to halt presurgical investigations due to concern of unfavorable post-surgical outcome. It also led in the same patient to discontinue long-standing carbamazepine therapy (a potentially aggravating drug in epilepsies due to SCN1A mutations), resulting in complete seizure control. Patients with pathogenic or likely pathogenic variants had a younger median age of seizure onset (range) compared to those without [18 months (8 months-18 years) vs 18 years (18 months-70 years), p = 0.02].

Significance

Our data demonstrate that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies in whom a genetic etiology is suspected. It can also influence clinical decision-making, including antiepileptic drug selection and consideration of epilepsy surgery, hence supporting its incorporation in the routine clinical care of this patient group.

Introduction

By accounting for 60% of all epilepsy cases, focal epilepsies are a clinically important group of disorders which have traditionally been regarded as being largely acquired (Thomas and Berkovic, 2014). It was thus somewhat surprising when the first epilepsy gene to be discovered was for focal epilepsy, identified in a large multiplex family with a rare autosomal dominant disorder (Steinlein et al., 1995). Despite this early hint that genetic factors may underlie focal epilepsies, gene discovery has been slow and genetic factors considered unlikely to be relevant to common focal epilepsies (Cavalleri et al., 2005, Thomas and Berkovic, 2014).

Recent advances in gene sequencing technologies have rekindled the interest in the genetics of focal epilepsies, leading to several important breakthroughs. A key discovery was that mutations in DEPDC5, which encodes a negative regulator of the mammalian target of rapamycin (mTOR) pathway, are a major cause of inherited focal epilepsies, including familial focal epilepsy with variable foci, autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, and other small families with non-lesional focal epilepsy (Dibbens et al., 2013, Ishida et al., 2013, Picard et al., 2014). DEPDC5 mutations can also result in focal epilepsy with brain malformations (Baulac et al., 2015, Scheffer et al., 2014). In addition, the role of established epilepsy genes in focal epilepsies has been reappraised. In a genome-wide association study, variation in SCN1A was found to increase susceptibility to mesial temporal lobe epilepsy associated with hippocampal sclerosis and febrile seizures (Kasperaviciute et al., 2013).

Whole exome sequencing (WES) is now commonplace in research endeavors and moving into clinical use, yet its utility for focal epilepsy in the ‘real-world’ setting has not been specifically determined. Here, we prospectively evaluated the diagnostic yield and management implications of WES, followed by targeted gene analysis, in patients with common focal epilepsies seen in everyday clinical practice.

Section snippets

Study design and participants

This was a prospective two-center study designed to assess the utility of incorporating WES in the routine care of patients with focal epilepsies in whom there was a justification for considering the possibility of a genetic cause. From February 10, 2014, to December 10, 2014, consecutive eligible patients seen at the epilepsy outpatient clinics or inpatient video-EEG monitoring units of the Royal Children’s Hospital and Royal Melbourne Hospital were invited to participate in the study.

Participants’ characteristics

Of 42 consecutive patients meeting eligibility criteria, 40 provided informed consent and were enrolled in the study. Twenty-four (60%) were males and 16 (40%) were females. Their median age (range) was 32.5 (2–74) years [12 children (i.e. age <18 years) and 28 adults], and median age of seizure onset (range) was 17.5 years (8 months–70 years). Most patients (n = 32, 80%) underwent brain MRI studies at 3T; the remaining 8 patients (20%) were imaged at 1.5T. Temporal lobe epilepsy was the most

Discussion

Driven by its high throughput and increased affordability, next-generation sequencing (NGS) is being increasingly applied in the clinical care of patients with various conditions, including epilepsy. Its clinical utility has been demonstrated in the epileptic encephalopaties, in neurodevelopmental disorders in which epilepsy is a comorbid feature, and in mixed epilepsy cohorts (Allen et al., 2016, Della Mina et al., 2015, Lemke et al., 2012, Mercimek-Mahmutoglu et al., 2015, Srivastava et al.,

Conclusions

Our study is a real-world application of one of the latest gene-sequencing technologies available in clinical practice to a cohort in which genetic testing is not usually part of the diagnostic work-up. We demonstrated that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies and can influence clinical decision-making, hence supporting its incorporation into routine care.

Funding

This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Program Grant (628952) to SFB and IES, a Practitioner Fellowship (1006110) to IES, and a R.D. Wright Career Development Fellowship (1063799) to MSH. The Melbourne Genomics Health Alliance (a collaboration jointly funded by the Royal Melbourne Hospital, Royal Children’s Hospital, University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Murdoch Childrens Research Institute, CSIRO

Conflicts of interest

Piero Perucca is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from the University of Melbourne, the Warren Haynes Neuroscience Research Fellowship from the The Royal Melbourne Hospital Neuroscience Foundation, and received honoraria from Eisai.

Ingrid E. Scheffer has served on a scientific advisory board for UCB; editorial boards of the Annals of Neurology, Neurology and Epileptic Disorders; may accrue

Acknowledgements

We are grateful to the patients and their families for participation in the study. We also thank the referring neurologists at the Royal Children’s Hospital and the Royal Melbourne Hospital; Ivan Macciocca, Gemma Brett, Ella Wilkins, Emma Creed (Melbourne Genomics Health Alliance) and Caitlin Bennett (Epilepsy Research Centre, University of Melbourne) for their assistance the study; and Elena Aleksoska (Epilepsy Research Centre, University of Melbourne) for performing genomic DNA extractions.

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