title: Rare copy number variants are an important cause of epileptic encephalopathies.
abstract: OBJECTIVE
  Rare copy number variants (CNVs)--deletions and duplications--have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed.
  
  
  METHODS
  We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused, whole-genome oligonucleotide array.
  
  
  RESULTS
  We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one-half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.
  
  
  CONCLUSIONS
  Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA. hmefford@u.washington.edu
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Simone C
authors.initials: SC
authors.lastname: Yendle
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hsu
authors.forename: Joseph
authors.initials: J
authors.lastname: Cook
authors.forename: Eileen
authors.initials: E
authors.lastname: Geraghty
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.forename: Orvar
authors.initials: O
authors.lastname: Eeg-Olofsson
authors.forename: Lynette G
authors.initials: LG
authors.lastname: Sadleir
authors.forename: Deepak
authors.initials: D
authors.lastname: Gill
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Mark
authors.initials: M
authors.lastname: Mackay
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: James T
authors.initials: JT
authors.lastname: Pelakanos
authors.forename: Ian
authors.initials: I
authors.lastname: Andrews
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wallace
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D015220:Calcium Channels / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: C531012:CACNA2D3 protein, human; D015220:Calcium Channels; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases