Abstracts

Rationale: The objective was evaluate the yield of clinical chromosomal microarray (CMA) testing in a retrospective series of patients with epilepsy, and to identify novel or rarely reported overlapping copy number variants (CNVs) in this population. Methods: We identified 977 patients with an ICD9 code for epilepsy or seizures who had a clinical CMA performed between October 2006 and February 2011 in the Children's Hospital Boston system. We retrospectively reviewed medical records to identify if the patients met clinical criteria for epilepsy and define abnormalities on CMA. Results: On review of records, 4 patients were excluded because CMA results were not in the chart and 167 patients were excluded because they did not have clinical epilepsy. Some excluded patients had febrile seizures only or evaluation for spells which were not thought to be seizures by the treating neurologist. Of the remaining 806 patients, the CMA showed at least one CNV in 324 patients (40%) and was normal in 482 (60%). The total number of CNVs was 437 (1-4 per patient) of which there were 183 deletions (42%) and 254 (58%) duplications. Thirty-five were confirmed as de novo, 183 were inherited, and inheritance was unknown in 219. Size ranged between 18 kb and 19 Mb, except one 142 Mb duplication and 3 chromosomal trisomies (X, 21, and 9). One hundred forty-seven CNVs were over 500 kb in size (33%). This series includes at least 5 deletions and 1 duplication involving known epilepsy related genes (KCNQ2, SCN1A, PLCB1, and CACNB4), and 24 CNVs in known hotspots for CNVs in idiopathic epilepsy (15q11.2, 15q13.3, 15q11-q13, 16p11.2, 16p13.11). It also includes CNVs associated with known syndromes that are associated with epilepsy such as Potocki-Lupski syndrome, Mowat-Wilson syndrome, Angelman syndrome, Williams-Beuren region reciprocal syndrome, MECP2 duplication syndrome, Phelan-McDermid syndrome, 22q11 duplication syndrome, 1p36 deletion syndrome, and 6q deletion syndrome. In addition, there are numerous CNVs that occur multiple times with overlap. These may have novel associations with epilepsy, but require further investigation and comparison with controls. For example there are three overlapping deletions involving Xp22.31 (859kb, 1.6 Mb, and 9.6 Mb in size), one de novo and two of unknown inheritance. There are two case reports in the literature of patients with deletions in this region and associated epilepsy and intellectual disability, one with cortical heterotopias. There are 5 overlapping duplications in the same region, ranging from 311 kb to 1.6 Mb in size. Conclusions: The yield of CMA testing in epilepsy patients is high, and not infrequently identifies known abnormalities associated with epilepsy. Further phenotypic evaluation of rare or novel repetitive CNVs is warranted and may identify new genotype- phenotype correlations or strengthen rarely reported genotype-phenotype associations. For example, data support the association of CNVs at Xp22.31 with epilepsy.