title: Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization.
abstract: OBJECTIVE
  To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  Epilepsy centers in Italy.
  
  
  METHODS
  Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization.
  
  
  METHODS
  Identification of copy number variations (CNVs) and gene enrichment.
  
  
  RESULTS
  Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy.
  
  
  CONCLUSIONS
  Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.
authors.affiliation: Laboratory of Neurogenetics, Department of Neuroscience, Institute G. Gaslini, Largo Gaslini 5, Genoa, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Antonietta
authors.initials: A
authors.lastname: Coppola
authors.forename: Roberta
authors.initials: R
authors.lastname: Paravidino
authors.forename: Michela
authors.initials: M
authors.lastname: Malacarne
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.forename: Angela
authors.initials: A
authors.lastname: Robbiano
authors.forename: Monica
authors.initials: M
authors.lastname: Traverso
authors.forename: Marianna
authors.initials: M
authors.lastname: Pezzella
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Belcastro
authors.forename: Amedeo
authors.initials: A
authors.lastname: Bianchi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Elia
authors.forename: Antonio
authors.initials: A
authors.lastname: Falace
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gazzerro
authors.forename: Edoardo
authors.initials: E
authors.lastname: Ferlazzo
authors.forename: Elena
authors.initials: E
authors.lastname: Freri
authors.forename: Roberta
authors.initials: R
authors.lastname: Galasso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gobbi
authors.forename: Cristina
authors.initials: C
authors.lastname: Molinatto
authors.forename: Simona
authors.initials: S
authors.lastname: Cavani
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Striano
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: Cavaliere
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Magi
authors.forename: Maria
authors.initials: M
authors.lastname: Piccione
authors.forename: Franca
authors.initials: F
authors.lastname: Dagna Bricarelli
authors.forename: Domenico A
authors.initials: DA
authors.lastname: Coviello
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019295:Computational Biology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics; D007558:Italy / Q000453:epidemiology; D008279:Magnetic Resonance Imaging; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009422:Nervous System Diseases / Q000453:epidemiology / Q000235:genetics; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D055815:Young Adult