1/2-Somatic mosaicism and autism spectrum disorder

1/2-躯体镶嵌和自闭症谱系障碍

• 批准号: 9246015
• 负责人: Peter J Park
• 金额: $ 10.17万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246015
• 关键词: Affect; American; Autopsy; Biological Neural Networks; Blood; Brain; Brain Diseases; Brain region; Cancer Etiology; Cell Nucleus; Cells; Child; Code; Complex; Copy Number Polymorphism; DNA; Data; Data Set; Detection; Development; Diagnostic tests; Disease; Elements; Embryonic Development; Epilepsy; Etiology; FMR1; Fertilization; Fragile X Syndrome; Frequencies; Genes; Genetic; Germ-Line Mutation; Goals; Health; Human; Individual; Inherited; Intellectual functioning disability; Interneurons; Laboratories; Lead; Maps; Methods; Modeling; Mosaicism; Mus; Mutate; Mutation; Mutation Analysis; Neurodevelopmental Disorder; Neurons; Nucleotides; Pathogenesis; Patients; Prevalence; Process; Regulatory Element; Reporting; Research; Resources; Role; Sampling; Schizophrenia; Site; Somatic Mutation; Sorting - Cell Movement; Specimen; TSC1/2 gene; Techniques; Testing; Tissue Banking; Tissue Banks; Transcript; Tuberous Sclerosis; Untranslated RNA; Variant; Work; associated symptom; autism spectrum disorder; base; brain cell; brain tissue; cell type; deep sequencing; disorder control; exome sequencing; fetal; frontal lobe; genetic disorder diagnosis; genome sequencing; improved; in vivo; induced pluripotent stem cell; insight; mouse model; neurodevelopment; neuropsychiatric disorder; next generation sequencing; novel; prevent; progenitor; risk variant; transcriptome; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): Somatic mutations are de novo mutations that occur after fertilization. Once a cell has acquired a somatic mutation, all of its progenitors will also carry that mutation. Thus, if a cell acquires a mutation early in embryonic development, the mutation will be carried by many of the cells in the body. However, if the mutation occurs late in development, then only a few cells might carry it. Thus, it is possible to have mutations that only occur in the brain, or a small region of the brain. It has been known for a while that somatic mutations can cause cancer, and recent studies are showing that somatic mutations are associated with neurodevelopmental disorders resembling autism spectrum disorders (ASDs) both in terms of their high de novo mutation rate and in terms of their associated symptoms such as intellectual disability and epilepsy. We hypothesize that somatic mutations represent a significant cause of (ASDs) because of the high rate of de novo mutations associated with ASDs, the importance of somatic mutations in some genes known to cause ASDs, and the importance of somatic mutations in other developmental brain disorders with features that overlap ASDs. The technical and resource limitations that had prevented a systematic study of the role of somatic mutations in ASDs have now been overcome thanks to 1] Next-Generation Sequencing (NGS), which allows for the deep sequencing of genes and their transcripts with the ability to analyze each sequence, and 2] tissue banks that have collected brain specimens from individuals who had ASD. In this collaborative UO1 we will employ complementary approaches to systematically identify and functionally characterize somatic brain mutations associated with ASD. For causative somatic mutations identified in ASD brain, we will use techniques developed in our labs to examine individual brain cells for the presence of somatic mutation. This will provide us with a map of what regions of the brain, and what cells types in the brain carry these somatic mutations. We will also model and functionally characterize ASD- associated brain mutations in induced pluripotent cells and mice. This study could 1] improve the genetic diagnosis of ASD; by assessing the prevalence of somatic mutations as a cause of ASD, 2] provide a paradigm that may apply to other complex neuropsychiatric diseases (such as schizophrenia), and 3] improve our understanding of the mechanisms underlying ASD by creating a map of brain regions and cell types involved in ASD.