title: 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.
authors.affiliation: Departments of Neurology and Pediatrics, Washington University, St Louis, MO, USA. arpac@u.washington.edu
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.forename: Liu Lin
authors.initials: LL
authors.lastname: Thio
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Marzena
authors.initials: M
authors.lastname: Gajecka
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Eric D
authors.initials: ED
authors.lastname: Marsh
authors.forename: Mattia
authors.initials: M
authors.lastname: Gentile
authors.forename: James D
authors.initials: JD
authors.lastname: Reggin
authors.forename: James W
authors.initials: JW
authors.lastname: Wheless
authors.forename: Sandhya
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Ravinesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Susan L
authors.initials: SL
authors.lastname: Christian
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Natalia
authors.initials: N
authors.lastname: Maltsev
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
mesh_terms: D002869:Chromosome Aberrations; D019295:Computational Biology; D018628:Gene Dosage; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016548:Prosencephalon / Q000002:abnormalities / Q000378:metabolism*; D013036:Spasms, Infantile / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics