Clinical Significance of Rare Copy Number Variations in Epilepsy: A Case-Control Survey Using Microarray-Based Comparative Genomic Hybridization

• Published in: Archives of neurology (Chicago) Vol. 69; no. 3; pp. 322 - 330
• Main Authors: Striano, Pasquale, Coppola, Antonietta, Paravidino, Roberta, Malacarne, Michela, Gimelli, Stefania, Robbiano, Angela, Traverso, Monica, Pezzella, Marianna, Belcastro, Vincenzo, Bianchi, Amedeo, Elia, Maurizio, Falace, Antonio, Gazzerro, Elisabetta, Ferlazzo, Edoardo, Freri, Elena, Galasso, Roberta, Gobbi, Giuseppe, Molinatto, Cristina, Cavani, Simona, Zuffardi, Orsetta, Striano, Salvatore, Ferrero, Giovanni Battista, Silengo, Margherita, Cavaliere, Maria Luigia, Benelli, Matteo, Magi, Alberto, Piccione, Maria, Dagna Bricarelli, Franca, Coviello, Domenico A, Fichera, Marco, Minetti, Carlo, Zara, Federico
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 01.03.2012
• Subjects: Adolescent; Adult; Age of Onset; Aged; Biological and medical sciences; Child; Child, Preschool; Cohort Studies; Computational Biology; Diagnostic and Statistical Manual of Mental Disorders; Epilepsy; Epilepsy - genetics; Female; Gene Deletion; Gene Dosage; Gene Duplication; Gene Rearrangement; Genes; Genome-Wide Association Study; Genomics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; In Situ Hybridization, Fluorescence; Intellectual disabilities; Intellectual Disability - epidemiology; Intellectual Disability - genetics; Italy - epidemiology; Magnetic Resonance Imaging; Male; Medical sciences; Medical screening; Microarray Analysis; Middle Aged; Nervous system (semeiology, syndromes); Nervous System Diseases - epidemiology; Nervous System Diseases - genetics; Neurology; Nucleic Acid Hybridization; Polymerase Chain Reaction; Prospective Studies; Young Adult; Italy; Survey; Nervous system diseases; Comparative genomic hybridization; Copy number; Epilepsy; Central nervous system disease; Cerebral disorder
• ISSN: 0003-9942; 2168-6149; 1538-3687; 1538-3687; 2168-6157
• DOI: 10.1001/archneurol.2011.1999

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 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.