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Rare copy number variants are an important cause of epileptic encephalopathies
Author(s) -
Mefford Heather C.,
Yendle Simone C.,
Hsu Cynthia,
Cook Joseph,
Geraghty Eileen,
McMahon Jacinta M.,
EegOlofsson Orvar,
Sadleir Lynette G.,
Gill Deepak,
BenZeev Bruria,
LermanSagie Tally,
Mackay Mark,
Freeman Jeremy L.,
Andermann Eva,
Pelakanos James T.,
Andrews Ian,
Wallace Geoffrey,
Eichler Evan E.,
Berkovic Samuel F.,
Scheffer Ingrid E.
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22645
Subject(s) - copy number variation , epilepsy , candidate gene , comparative genomic hybridization , cohort , biology , genetics , phenotype , gene , medicine , genome , pathology , neuroscience
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. Interpretation: 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. ANN NEUROL 2011;70:974–985