Megalencephaly and segmental brain overgrowth in humans

人类巨脑畸形和节段性大脑过度生长

• 批准号: 8941302
• 负责人: William B. Dobyns
• 金额: $ 68.02万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8941302
• 关键词: AKT Signaling Pathway; AKT3 gene; Accounting; Address; Affect; Antibodies; Autistic Disorder; Bilateral; Biology; Birth; Brain; CCND2 gene; Candidate Disease Gene; Cells; Cerebral cortex; Child; Childhood; Clinical; Common Data Element; Congenital Abnormality; Cortical Dysplasia; Cortical Malformation; DNA; Data; Data Analyses; Development; Disease; Drug Targeting; Dysplasia; EZH2 gene; Electroencephalography; Enrollment; Epilepsy; Future; Genes; Genetic; Genetic study; Genomics; Genotype; Goals; Hand; Head; Health; Histopathology; Human; Hydrocephalus; Image; Immunohistochemistry; Individual; Intellectual functioning disability; Knowledge; Lead; Link; Malignant Neoplasms; Megalencephaly; Methods; Molecular; Mosaicism; Mutant Strains Mice; Mutation; Natural History; Nature; Outcome Measure; PIK3CA gene; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Protein Array; Proteomics; Proto-Oncogene Proteins c-akt; Reading; Risk Factors; Role; Sampling; Seizures; Sequence Analysis; Severity of illness; Signal Pathway; Signaling Molecule; Skin; Source; Specimen; Syndrome; Technology; Testing; Therapeutic Trials; Tissue Sample; Tissues; Validation; Variant; Weight; Work; cohort; deep sequencing; developmental disease; effective therapy; exome; functional status; gene discovery; genome sequencing; laser capture microdissection; malformation; mutant; public health relevance; targeted sequencing

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：巨脑畸形（MEG）或“大脑”是一种与大脑过度生长、频繁的皮质畸形和不同程度的智力障碍、自闭症、癫痫、脑积水、Chiari 畸形以及许多其他发育和发育障碍相关的发育障碍。 MEG 历来被认为与半侧巨脑畸形和局灶性皮质发育不良 (FCD) 不同，但最近的遗传学研究发现了相同基因的突变。所有这些基因都在 PI3K-AKT 细胞内信号通路中发挥作用，特别是 PIK3CA、PIK3R2、PTEN、AKT3 和 CCND2。我们招募了 400 多名 MEG-HEG-FCD 综合征儿童，其中 10% 的儿童存在这 5 个基因的突变。到 75%，具体取决于具体的综合征。在这个项目中，我们建议更好地定义表型，进行详细的基因型-表型分析，检查通过免疫组织化学和反相蛋白阵列检测 PI3K-AKT 和其他信号通路，对已知和强候选基因进行深度靶向测序，研究镶嵌现象的影响，并使用全外显子组和全基因组测序寻找其他致病基因。