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.

The clustering of functionally related genes contributes to CNV-mediated disease

“…Large CNVs (typically >500 kb) have been consistently associated with disease (Sharp et al 2006;Sebat et al 2007;Xu et al 2008;Greenway et al 2009;Kirov et al 2009;Miller et al 2010;Cooper et al 2011;Paciorkowski et al 2011;Girirajan et al 2013), but similarly sized CNVs are not uncommon and are found at frequencies of 5%-10% in the healthy population (Itsara et al 2009). If the pathogenicity of a CNV is increased by perturbing multiple functionally related genes, then we would expect large CNVs in healthy individuals to avoid such clusters.…”

Genotype–phenotype correlation in interstitial 6q deletions: a report of 12 new cases

“…Due to the observation of infantile spasms and other epilepsy phenotypes, we compared the brain expressed genes to the Arx conditional knockout transcriptome list [43] and genes in synapse development and function (GO:0045202 and children), as these pathways have recently been associated with infantile spasm pathogenesis [44]. Due to the observation of cerebellar malformations, we also compared the brain-expressed genes for relationships with genes involved in cerebellar development and function (GO:0021549 plus those extracted from expert reviews [45,46]).…”

A survey of seizures and current treatments in 15q duplication syndrome

“…6,8,31,32 Infantile spasms are associated with maternally inherited duplications of 15q11-q13, suggesting a role for GABAergic synapses and postsynaptic density in the etiology of Dup15q seizure semiology. 33 Idic (15) is characterized by developmental delay, severe epilepsy, moderate-to-severe intellectual disability, early central hypotonia, autistic behavior, absent or poor language (e.g., marked echolalia), and minor dysmorphic features (e.g., down-slanting palpebral fissures, epicanthal folds, low-set ears, "coarse" facial features, and hypopigmented areas of the skin). 29,30 Metabolic workup and intracranial magnetic resonance imaging (MRI) are typically normal and characterization of seizures is limited in prior studies, which describe early onset of treatment-refractory epilepsy evolving into a Lennox-Gastaut syndrome (LGS) phenotype.…”