Genomic copy number variations at 17p13.3 and epileptogenesis

Summary

Deletion of the terminal end of 17p is responsible for Miller-Dieker syndrome (MDS), which is characterized by lissencephaly, distinctive facial features, growth deficiency, and intractable seizures. Using microarray-based comparative genomic hybridization, 3 patients with epilepsy were revealed to have genomic copy number aberrations at 17p13.3: a partial LIS1 deletion in a patient with isolated lissencephaly and epilepsy, a triplication of LIS1 in a patient with symptomatic West syndrome, and a terminal deletion of 17p including YWHAE and CRK but not LIS1 in a patient with intractable epilepsy associated with distinctive facial features and growth retardation. In this study, it was suggested that the identified gain or loss of genomic copy numbers within 17p13.3 result in epileptogenesis and that triplication of LIS1 can cause symptomatic West syndrome.

Introduction

The terminal end of the short arm of chromosome 17 is crucial for neurodevelopment and deletion of this region is associated with Miller-Dieker syndrome (MDS), a congenital malformation syndrome consisting of typical lissencephaly and distinctive facial features. Patients with MDS also show growth deficiency, severe developmental delays, and intractable seizures (Dobyns et al., 1991). MDS results from chromosomal disruption, including cytogenetically visible or submicroscopic deletions of the 17p13.3 region, which includes LIS1, a key indicator of MDS (Dobyns et al., 1993, Reiner et al., 1993). LIS1 encodes PAFAH1B1 and participates in neural migration, disruption of which is responsible for lissencephaly. Independent LIS1 deletions or nucleotide alterations in its coding exons cause isolated lissencephaly without growth deficiency or distinctive facial features (Cardoso et al., 2000). This finding indicates that the clinical manifestations associated with MDS patients, such as growth deficiency and dysmorphic features, are likely derived from other genes included in the 17p13.3 region. Genotype–phenotype correlation studies in patients with deletions in the terminal region of 17p revealed that LIS1 deletion is responsible for lissencephaly and that combined deletion of LIS1 and YWHAE results in severer lissencephaly and a distinctive facial appearance, the hallmarks of MDS (Cardoso et al., 2003).

Recent revolutionary technological advances in molecular cytogenetics have enabled us to identify submicroscopic chromosomal abnormalities including gain or loss of genomic copy numbers (Emanuel and Saitta, 2007). Such genomic copy number variations (CNV) have only recently been identified using microarray-based comparative genomic hybridization (aCGH), and the incidence of such abnormalities seems to be more frequent than was thought prior to the human genome project (Shaffer et al., 2007). Genomic duplications are of particular interest because many submicroscopic duplications have been shown to be related to neurological disorders, including developmental delay and epilepsy (Lee and Lupski, 2006). Small genomic deletions and duplications have also been reported in 17p13.3 (Bi et al., 2009, Haverfield et al., 2009, Mei et al., 2008, Mignon-Ravix et al., 2009, Roos et al., 2009, Sreenath Nagamani et al., 2009).

In this study, we identified three types of genomic CNVs in the chromosome 17p13.3 region in 3 patients with epilepsy. This result implicates the dose effects of the genes in the 17p terminal region in epilepsy.