Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function

Abstract

Infantile spasms (ISS) are an epilepsy disorder frequently associated with severe developmental outcome and have diverse genetic etiologies. We ascertained 11 subjects with ISS and novel copy number variants (CNVs) and combined these with a new cohort with deletion 1p36 and ISS, and additional published patients with ISS and other chromosomal abnormalities. Using bioinformatics tools, we analyzed the gene content of these CNVs for enrichment in pathways of pathogenesis. Several important findings emerged. First, the gene content was enriched for the gene regulatory network involved in ventral forebrain development. Second, genes in pathways of synaptic function were overrepresented, significantly those involved in synaptic vesicle transport. Evidence also suggested roles for GABAergic synapses and the postsynaptic density. Third, we confirm the association of ISS with duplication of 14q12 and maternally inherited duplication of 15q11q13, and report the association with duplication of 21q21. We also present a patient with ISS and deletion 7q11.3 not involving MAGI2. Finally, we provide evidence that ISS in deletion 1p36 may be associated with deletion of KLHL17 and expand the epilepsy phenotype in that syndrome to include early infantile epileptic encephalopathy. Several of the identified pathways share functional links, and abnormalities of forebrain synaptic growth and function may form a common biologic mechanism underlying both ISS and autism. This study demonstrates a novel approach to the study of gene content in subjects with ISS and copy number variation, and contributes further evidence to support specific pathways of pathogenesis.

Figure 1

Genomic data on seven subjects with deletion 1p36 and ISS (Del 1p36-ISS Cohort), comparing breakpoints with a previously reported subject (ISS reported), a subject with ISS and PMG, the PMG critical region, and five interstitial deletions without ISS but other forms of epilepsy variable. The region within the dashed line indicates plausible ISS critical region containing GABRD, with the solid region representing a smaller hypothesized critical region containing the synaptic-expressed KLHL17.

Figure 2

(a) The expanded gene regulatory network for ventral forebrain development. ISS-associated genes are indicated by closed circles, candidate members of the network identified in this study are indicated by dashed circles. In the color version, red indicates gene deletion or intragenic mutation and green indicates gene duplication. Dashed lines represent putative gene regulatory relationships that require further validation. Figure generated using BioTapestry (http://www.biotapestry.org/). (b) Illustration of the GABA-receptor subunit genes expressed in the post-synapse with abnormal copy number in subjects with ISS identified in this study. The involvement of STXBP1 in synaptic vesicle exocytosis is also shown. Figure generated using ProteinLounge (http://www.proteinlounge.com/). GABA, gamma-aminobutyric acid; MGE, medial ganglionic eminence. The color reproduction of this figure is available at the European Journal of Human Genetics journal online.

Figure 3

(a) Protein–protein interaction network of synaptic vesicle exocytosis (GO:0016079), illustrating a relationship between ISS candidate SNPH with STX1A, which in turn interacts with the ISS-associated STXBP1. (b) Protein–protein interaction network of the postsynaptic density (GO:0014069), illustrating a relationship between ERBB4 with DLG4, which in turn interacts with the ISS-associated GRIN1 and GRIN2A.