Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy
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.
References (26)
- et al.
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy
Genet. Med.
(2016) - et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Genet. Med.
(2015) - et al.
Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion
Epilepsia
(2016) - et al.
A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1
Science
(2013) - et al.
Co-occurring malformations of cortical development and SCN1A gene mutations
Epilepsia
(2014) - et al.
Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
Ann. Neurol.
(2015) - et al.
Diagnostic clinical genome and exome sequencing
N. Engl. J. Med.
(2014) - et al.
Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?
Brain
(2005) - et al.
Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform
Eur. J. Hum. Genet.
(2015) - et al.
Mutations in DEPDC5 cause familial focal epilepsy with variable foci
Nat. Genet.
(2013)
The pharmacogenomics of epilepsy
Expert Rev. Neurother.
Mutations of DEPDC5 cause autosomal dominant focal epilepsies
Nat. Genet.
Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A
Brain
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