Rare copy number variants are an important cause of epileptic encephalopathies

Abstract

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.

Figure 1. Overlapping deletions of 7q21 in two probands

A) Pedigree for proband T438, who has a ~4 Mb deletion of 7q21. The proband’s mother and three children, who have all had one or more seizures, also have the same deletion. B) Array CGH data for T438 and T964. The red box highlights the region on 7q21 that is deleted in both patients. X-axis represents genomic coordinates (chr7: 73.5–83.5 Mb, NCBI Build 36). For each individual, deviations of probe log2 ratios from zero are depicted by vertical grey/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively. Genes are represented by blue lines at the bottom. MAE = Epilepsy with myoclonic-atonic seizures; FS = febrile seizures; FS+ = febrile seizures plus; GGE = genetic generalized epilepsies; DEL = deletion; NT = not tested

Figure 2. Recurrent duplications of 16p11.2 in two probands

A) Pedigree for proband T16335, who has a duplication of 16p11.2. The duplication in inherited from his father and also present in his sister with West syndrome. B) Array CGH data for T16335 and T2547, with log₂ ratios displayed as in Figure 1. JME = juvenile myoclonic epilepsy; DUP = duplication

Figure 3. Copy number changes affecting neuronal genes of interest

A) 700-kb de novo duplication of 1q32 in patient T3810. B) 300-kb deletion of 5p13 involving the ADAM23 gene in T18349. Array CGH data displayed as in Figures 1 and 2.