TY - JOUR
T1 - Copy number variants and infantile spasms
T2 - Evidence for abnormalities in ventral forebrain development and pathways of synaptic function
AU - Paciorkowski, Alex R.
AU - Thio, Liu Lin
AU - Rosenfeld, Jill A.
AU - Gajecka, Marzena
AU - Gurnett, Christina A.
AU - Kulkarni, Shashikant
AU - Chung, Wendy K.
AU - Marsh, Eric D.
AU - Gentile, Mattia
AU - Reggin, James D.
AU - Wheless, James W.
AU - Balasubramanian, Sandhya
AU - Kumar, Ravinesh
AU - Christian, Susan L.
AU - Marini, Carla
AU - Guerrini, Renzo
AU - Maltsev, Natalia
AU - Shaffer, Lisa G.
AU - Dobyns, William B.
N1 - 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.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - autism
KW - bioinformatics
KW - copy number variation
KW - deletion 1p36 syndrome
KW - infantile spasms
UR - http://www.scopus.com/inward/record.url?scp=80955146569&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2011.121
DO - 10.1038/ejhg.2011.121
M3 - Article
C2 - 21694734
AN - SCOPUS:80955146569
SN - 1018-4813
VL - 19
SP - 1238
EP - 1245
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 12
ER -