Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function
- PMID: 21694734
- PMCID: PMC3230360
- DOI: 10.1038/ejhg.2011.121
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.
Figures
Similar articles
-
Novel copy number variations and phenotypes of infantile epileptic spasms syndrome.Clin Genet. 2024 Aug;106(2):161-179. doi: 10.1111/cge.14520. Epub 2024 Mar 28. Clin Genet. 2024. PMID: 38544467
-
Molecular characterization of a cohort of 73 patients with infantile spasms syndrome.Eur J Med Genet. 2015 Feb;58(2):51-8. doi: 10.1016/j.ejmg.2014.11.007. Epub 2014 Dec 11. Eur J Med Genet. 2015. PMID: 25497044
-
A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.BMC Med Genet. 2014 May 29;15:62. doi: 10.1186/1471-2350-15-62. BMC Med Genet. 2014. PMID: 24885232 Free PMC article.
-
Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013.Brain Dev. 2014 Oct;36(9):739-51. doi: 10.1016/j.braindev.2013.10.008. Epub 2013 Nov 20. Brain Dev. 2014. PMID: 24268986 Review.
-
Genetic and biologic classification of infantile spasms.Pediatr Neurol. 2011 Dec;45(6):355-67. doi: 10.1016/j.pediatrneurol.2011.08.010. Pediatr Neurol. 2011. PMID: 22114996 Free PMC article. Review.
Cited by
-
Autism-related KLHL17 and SYNPO act in concert to control activity-dependent dendritic spine enlargement and the spine apparatus.PLoS Biol. 2023 Aug 31;21(8):e3002274. doi: 10.1371/journal.pbio.3002274. eCollection 2023 Aug. PLoS Biol. 2023. PMID: 37651441 Free PMC article.
-
Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis.J Pers Med. 2022 Jun 20;12(6):1013. doi: 10.3390/jpm12061013. J Pers Med. 2022. PMID: 35743796 Free PMC article.
-
KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement.J Biomed Sci. 2020 Dec 1;27(1):103. doi: 10.1186/s12929-020-00696-1. J Biomed Sci. 2020. PMID: 33256713 Free PMC article.
-
Control of craniofacial and brain development by Cullin3-RING ubiquitin ligases: Lessons from human disease genetics.Exp Cell Res. 2020 Nov 15;396(2):112300. doi: 10.1016/j.yexcr.2020.112300. Epub 2020 Sep 26. Exp Cell Res. 2020. PMID: 32986984 Free PMC article. Review.
-
FOXG1-Related Syndrome: From Clinical to Molecular Genetics and Pathogenic Mechanisms.Int J Mol Sci. 2019 Aug 26;20(17):4176. doi: 10.3390/ijms20174176. Int J Mol Sci. 2019. PMID: 31454984 Free PMC article. Review.
References
-
- Lux AL, Osborne JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group. Epilepsia. 2004;45:1416–1428. - PubMed
-
- Saemundsen E, Ludvigsson P, Rafnsson V. Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia. 2008;49:1865–1870. - PubMed
-
- Saitsu H, Kato K, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782–788. - PubMed
-
- Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev. 2002;24:266–268. - PubMed
-
- Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB. Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology. 2003;61:267–276. - PubMed
Publication types
MeSH terms
Grants and funding
LinkOut - more resources
Full Text Sources
Medical