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Human genetics and molecular mechanisms of congenital hydrocephalus

先天性脑积水的人类遗传学和分子机制

基本信息

批准号：
9887754
负责人：
Kristopher Kahle
金额：
$ 51.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9887754
关键词：
Accounting Affect Biological Biological Models Biology Birth Brain Brain Diseases CRISPR/Cas technology Candidate Disease Gene Case Study Cerebral Ventricles Cerebrospinal Fluid Cerebrospinal fluid shunts procedure Cilia Clinical Clinical Management Congenital Hydrocephalus Copy Number Polymorphism Coupling DNA sequencing Data Development Diagnostic Differentiation and Growth Disease Embryo Etiology Evaluation Family Frequencies Future Gene Expression Gene Mutation Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genomic approach Heterogeneity Homeostasis Homologous Gene Human Human Genetics Hydrocephalus Immunohistochemistry Impairment In Situ Hybridization International Knowledge Lead Live Birth Measures Mediating Methods Modeling Molecular Morbidity - disease rate Mus Mutant Strains Mice Mutation Nature Neural Cell Adhesion Molecule L1 Neural Tube Development Neurodevelopmental Disorder Neurons Nucleotides Ontology Operative Surgical Procedures Optical Coherence Tomography Parents Pathogenesis Pathway interactions Patients Pattern Phenotype Preventive Rana Research SMARCC1 gene Social support Stem Cell Development Structure Testing Therapeutic Time Transgenic Organisms Validation Variant Work Xenopus autism spectrum disorder base bioinformatics pipeline case control cerebrospinal fluid flow clinical decision-making cohort cost effective de novo mutation exome sequencing experience functional genomics gene discovery genetic approach genetic architecture genetic pedigree human fetal brain improved in silico in vivo insight knock-down mortality mouse model mutant nerve stem cell neurogenesis next generation novel novel diagnostics novel therapeutics overexpression particle proband prognostic recruit screening segregation stem cell fate targeted sequencing tool ventricular system

项目摘要

PROJECT SUMMARY Congenital hydrocephalus (CH), the primary enlargement of the cerebrospinal (CSF)-filled brain ventricles, affects 1/1000 births and is a major cause of morbidity and mortality. Although ~60% of all CH cases are predicted to have a genetic etiology, known genes account for <5% of CH cases. Significant gaps in our understanding of the molecular pathogenesis of CH impede the development of preventive, diagnostic, and therapeutic measures. Fundamental obstacles to CH gene discovery using traditional genetic approaches include locus heterogeneity, phenotypic complexity, and the sporadic nature of the majority of CH cases. Whole exome sequencing (WES) has the potential to overcome these obstacles and has led to unprecedented opportunities for gene discovery in autism and structural brain disorders. We recently used WES to identify four novel CH genes, accounting for ~10% of studied CH cases (Furey et al., Neuron, 2018). All four genes are required for neural tube development and regulate neural stem cell (NSC) fate. These results implicate impaired neurogenesis, rather than CSF over-accumulation, in the pathogenesis of a significant subset of CH patients, with potentially paradigm-changing diagnostic and therapeutic implications. As many causal CH genes remain undiscovered, our objective here is to utilize a functional genomics approach to discover, validate, and gain mechanistic insight into newly identified CH-causing mutations. Our hypothesis is that WES will identify multiple novel CH genes, many of which will converge on pathways that regulate the NSC development. Based on our experience that has been successful in identifying several CH and structural brain disorder genes over the past several years, we now propose to ascertain additional sporadic CH case-parent trios and Turkish consanguineous familial CH forms and perform WES on our large, well-phenotyped CH cohort to discover novel de novo and transmitted CH gene mutations. This will be followed by analyses to determine the expression patterns of newly identified prioritized genes during mammalian brain development. We will then rapidly and inexpensively functionally screen prioritized CH candidate gene mutations for their ability to recapitulate hydrocephalus using our novel, validated platform that utilizes live Xenopus embryos, CRISPR/Cas9 gene editing, quantitative optical coherence tomography, and real-time CSF particle tracking (Date et al., Sci Rep, 2019, Accepted). For select validated genes, we will establish Xenopus lines to elucidate the biological consequences of human CH mutations on cilia-regulated CSF dynamics and NSC growth/differentiation and patterning. This functional genomics approach will elucidate the genetic architecture of CH, and set the stage for more detailed future biological studies in mouse models beyond the scope of this proposal. Ultimately, such knowledge has the potential to improve clinical management, prognostication, surveillance, and genetic advice; stimulate research into new non-surgical therapies; and improve the quality of our support for CH patients and their families.

项目总结