title: Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy.
abstract: 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.
  
  
  
  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.
  
  
  
  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].
  
  
  
  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.
authors.affiliation: Departments of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia. Electronic address: piero.perucca@mh.org.au.
authors.forename: Piero
authors.initials: P
authors.lastname: Perucca
authors.affiliation: Epilepsy Research Centre and Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: A Simon
authors.initials: AS
authors.lastname: Harvey
authors.affiliation: Department of Genetic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.affiliation: Centre for Translational Pathology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.affiliation: Melbourne Genomics Health Alliance, Melbourne, VIC, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Thorne
authors.affiliation: Melbourne Genomics Health Alliance, Melbourne, VIC, Australia; Departments of Medicine and Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Clara
authors.initials: C
authors.lastname: Gaff
authors.affiliation: Epilepsy Research Centre and Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Regan
authors.affiliation: Epilepsy Research Centre and Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Epilepsy Research Centre and Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Epilepsy Research Centre and Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Departments of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Departments of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011446:Prospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods; D000073359:Exome Sequencing / Q000379:methods*; D055815:Young Adult
keywords: Epilepsy; Focal; Genetic testing; Genetics; Seizures