Megalencephaly (MEG) or large brain is a developmental disorder associated with brain overgrowth, frequent cortical malformations, and variable intellectual disability, autism, epilepsy, hydrocephalus, Chiari malformation, and a host of other developmental and health problems. MEG has historically been considered as distinct from hemimegalencephaly and focal cortical dysplasia (FCD). However, recent genetic studies have identified mutations of the same genes that all function in the PI3K-AKT intracellular signaling pathway, especially PIK3CA, PIK3R2, PTEN, AKT3 and CCND2. We have enrolled a cohort of more than 400 children with MEG-HEG-FCD syndromes, with mutations of these 5 genes found in 10% to 75% depending on the specific syndrome. In this project, we propose to better define the phenotype, perform detailed genotype-phenotype analysis, examine the PI3K-AKT and other signaling pathways by immunohistochemistry and reverse phase protein arrays, perform deep targeted sequencing for both known and strong candidate genes, study the effects of mosaicism, and search for additional causative genes using whole exome and whole genome sequencing.
Megalencephaly (MEG) is a developmental disorder associated with an abnormally large brain, birth defects of the cerebral cortex, and variable intellectual disability, autism, epilepsy, and hydrocephalus. It is closely related to focal corticl dysplasia, one of the most common causes of intractable childhood epilepsy. We propose to study the clinical nature and genetic causes of these disorders, which are potentially treatable with specific drugs.
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