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

Piero Perucca, Ingrid E. Scheffer, A. Simon Harvey, Paul A. James, Sebastian Lunke, Natalie Thorne, Clara Gaff, Brigid M. Regan, John A. Damiano, Michael S. Hildebrand, Samuel F. Berkovic, Terence J. O'Brien, Patrick Kwan

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79 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalEpilepsy Research
Publication statusPublished - 1 Mar 2017
Externally publishedYes


  • Epilepsy
  • Focal
  • Genetic testing
  • Genetics
  • Seizures

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