Table of Contents

ABSTRACT

From analysis of copy number variations (CNVs) in a genome-wide association study (GWAS) of symptomatic epilepsy, we discovered a 1.36 megabase deletion at chromosome 18q21.32 in a patient with borderline intellectual disability, multiple cerebral cavernous malformations (CMs), and complex partial seizures from age one year. The deletion was confirmed by quantitative polymerase chain reaction. The deleted region included the genes ALPK2, MALT1, ZNF532, GRP, RAX, CPLX4, LMAN1, and CCBE1. GRP (gastrin-releasing peptide, or bombesin) and GRP receptor are expressed in the hippocampus, where GRP depolarizes GABAergic interneurons, thus inhibiting CA1 pyramidal neurons and suppressing seizures. GRP receptor gene disruption has previously been reported in a patient with epilepsy and low intelligence. We speculate that the combined effects of multiple CMs and decreased GRP may have induced epilepsy in this patient. The finding of both genetic and structural abnormalities that could have resulted in epilepsy independently and interactively in this patient illustrates the challenge in classifying epilepsy syndromes.

Keywords: epilepsy, genetics, copy number variant, 18q deletion, cerebral cavernous malformation, cavernoma, GRP, bombesin