title: Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.
abstract: To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy.
  
  
  
  In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis.
  
  
  
  Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%). A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications.
  
  
  
  DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.Genet Med 18 9, 898-905.
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Katherine L
authors.identifier: 0000-0001-8249-0549
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell Hagman
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Mroske
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Zöe
authors.initials: Z
authors.lastname: Powis
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D034281:Dynamins; D004827:Epilepsy / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D057089:Pathology, Molecular; D014157:Transcription Factors / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods
chemical_list: C529610:COQ4 protein, human; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C501130:PURA protein, human; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins