Clinical significance of rare copy number variations in epilepsy: A case-control survey using microarray-based comparative genomic hybridization

Pasquale Striano, Antonietta Coppola, Roberta Paravidino, Michela Malacarne, Stefania Gimelli, Angela Robbiano, Monica Traverso, Marianna Pezzella, Vincenzo Belcastro, Amedeo Bianchi, Maurizio Elia, Antonio Falace, Elisabetta Gazzerro, Edoardo Ferlazzo, Elena Freri, Roberta Galasso, Giuseppe Gobbi, Cristina Molinatto, Simona Cavani, Orsetta ZuffardiSalvatore Striano, Giovanni Battista Ferrero, Margherita Silengo, Maria Luigia Cavaliere, Matteo Benelli, Alberto Magi, Maria Piccione, Franca Dagna Bricarelli, Domenico A. Coviello, Marco Fichera, Carlo Minetti, Federico Zara

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. Design: Prospective cohort study. Setting: Epilepsy centers in Italy. Patients: 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. Main Outcomes Measures: 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 CNVslarger 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 associatedwith 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 betweenCNVsobserved 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.

Original languageEnglish
Pages (from-to)322-330
Number of pages9
JournalArchives of Neurology
Volume69
Issue number3
DOIs
Publication statusPublished - Mar 2012

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

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