Rare copy number variants are an important cause of epileptic encephalopathies
Article first published online: 21 DEC 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 6, pages 974–985, December 2011
How to Cite
Mefford, H. C., Yendle, S. C., Hsu, C., Cook, J., Geraghty, E., McMahon, J. M., Eeg-Olofsson, O., Sadleir, L. G., Gill, D., Ben-Zeev, B., Lerman-Sagie, T., Mackay, M., Freeman, J. L., Andermann, E., Pelakanos, J. T., Andrews, I., Wallace, G., Eichler, E. E., Berkovic, S. F. and Scheffer, I. E. (2011), Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol., 70: 974–985. doi: 10.1002/ana.22645
- Issue published online: 21 DEC 2011
- Article first published online: 21 DEC 2011
- Accepted manuscript online: 10 OCT 2011 10:45AM EST
- Manuscript Accepted: 26 AUG 2011
- Manuscript Revised: 18 AUG 2011
- Manuscript Received: 21 MAY 2011
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.
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.
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.
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