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

Alex R. Paciorkowski, Liu Lin Thio, Jill A. Rosenfeld, Marzena Gajecka, Christina A. Gurnett, Shashikant Kulkarni, Wendy K. Chung, Eric D. Marsh, Mattia Gentile, James D. Reggin, James W. Wheless, Sandhya Balasubramanian, Ravinesh Kumar, Susan L. Christian, Carla Marini, Renzo Guerrini, Natalia Maltsev, Lisa G. Shaffer, William B. Dobyns

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1238-1245
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number12
StatePublished - Dec 2011
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank the families of the subjects who enrolled in this study. The study was supported by grants from the National Institutes of Health including NINDS Neurologic Sciences Academic Development Award K12 NS001690-12 to ARP and R01-NS046616 to WBD; Washington University Children’s Discovery Institute, Grant MD-F-2010-62 to ARP; and the Ministry of Education and Science, Poland, Grant NN 301238836 to MG.


  • autism
  • bioinformatics
  • copy number variation
  • deletion 1p36 syndrome
  • infantile spasms


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