The Genetic Basis of Mid-Hindbrain Malformations

中后脑畸形的遗传基础

• 批准号: 8277226
• 负责人: William B. Dobyns
• 金额: $ 79.89万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277226
• 关键词: Affect; Animal Model; Autistic Disorder; Bioinformatics; Biological; Biological Models; Biological Process; Birth; Brain; Brain Stem; Candidate Disease Gene; Centers for Disease Control and Prevention (U.S.); Cerebellar malformation; Cerebellar vermis structure; Cerebellum; Code; Complex; Computer Analysis; Congenital cerebellar hypoplasia; Counseling; Dandy-Walker Syndrome; Data; Data Linkages; Databases; Development; Diagnosis; Diffuse; Disease; Disease Association; Embryo; Epilepsy; Family; Finding by Cause; Frequencies; Functional RNA; Future; Gene Proteins; Genes; Genetic; Genome; Goals; Grant; Human; In Vitro; Individual; Joubert syndrome; Lead; Maps; Mental Retardation; Mesenchymal; Mesenchyme; Methods; Midbrain structure; Modeling; Molar tooth; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Network-based; Pathway interactions; Patients; Phenotype; Posterior Fossa; Recruitment Activity; Reporting; Resolution; Resources; Seeds; Signal Transduction; Structure; Syndrome; Testing; Time; Transgenic Mice; Validation; Variant; Work; base; cisterna magna; cohort; developmental disease; gene discovery; genetic linkage analysis; genome-wide linkage; hindbrain; human subject; improved; in vitro Assay; infancy; insight; malformation; mouse model; mutant; network models; novel; overexpression; programs; public health relevance

DESCRIPTION (provided by applicant): Our general goal for this project is to advance our understanding of human developmental disorders that involve the brainstem and cerebellum - brain structures derived from the embryonic midbrain and hindbrain - that affect a minimum of 2.4 per 1000 resident births based on data from the CDC. Importantly, this large class of disorders co-occurs with more common developmental disorders such as autism, mental retardation and some forms of infantile epilepsy, and shares some of the same causes. With this renewal, we propose to expand the scope of our work beyond single phenotypes and genes to focus on delineating the critical phenotype spectra to which the most common MHM belong, and defining the underlying biological networks that are disrupted. To pursue these goals, we will use our large and growing cohort of human subjects to map additional MHM loci using SNP microarrays that provide both high-resolution autozygosity and linkage data in informative families as well as detect critical copy number variants in sporadic subjects. The causative genes will be identified using traditional Sanger or new high-throughput sequencing methods as appropriate abased on size of the critical region. We will use these and other known MHM causative genes to construct and revise model biological networks of genes and proteins, and test these genes and networks in additional patients as a candidate gene or more accurately a candidate network approach. These approaches need to be supported by ongoing active subject recruitment, as studies of comparable disorders such as mental retardation and autism have benefited from even larger numbers of subjects that we have so far collected. We need to use new high- throughput sequencing methods to more efficiently test larger critical regions, and to test entire gene networks rather than individual genes in matched cohorts of subjects. At every step - phenotype analysis, CNV analysis, model network construction and high-throughput sequencing - we will need expanded bioinformatics capabilities. Finally, we need to test the biological function of new genes and networks to support our gene identification studies. We expect that these studies will contribute immediately to more accurate diagnosis and counseling, and over time will lead to development of specific treatments for a subset of these disorders. We further expect that studies of mid-hindbrain development will have broad significance for human developmental disorders generally, providing compelling evidence for a connection between cerebellar development and other classes of developmental disorders such as autism, mental retardation and epilepsy. PUBLIC HEALTH RELEVANCE: Developmental disorders of the brainstem and cerebellum - which are derived from the embryonic midbrain and hindbrain - are a collectively important class of disorders that affect a minimum of 2.4 per 1000 resident births based on data from the CDC. The true frequency is likely much higher. This large class of disorders co-occurs with more common developmental disorders such as autism, mental retardation and some forms of infantile epilepsy, and shares some of the same causes. We propose to find the causes of several different types of brainstem and cerebellar malformations, which will contribute to more accurate diagnosis and counseling in the short term, and to specific treatments for some of these disorders in the long term.

描述（由申请人提供）：我们该项目的总体目标是增进我们对涉及脑干和小脑（源自胚胎中脑和后脑的大脑结构）的人类发育障碍的理解，每 1000 名居民出生中至少影响 2.4 例。 CDC 的数据。重要的是，这一大类疾病与更常见的发育障碍（例如自闭症、智力低下和某些形式的婴儿癫痫）同时发生，并且具有一些相同的原因。通过这次更新，我们建议将我们的工作范围扩大到单一表型和基因之外，重点描绘最常见的 MHM 所属的关键表型谱，并定义被破坏的潜在生物网络。 为了实现这些目标，我们将利用我们庞大且不断增长的人类受试者群体，使用 SNP 微阵列绘制额外的 MHM 基因座，该微阵列可提供信息丰富的家族中的高分辨率自合性和连锁数据，并检测散发受试者中的关键拷贝数变异。根据关键区域的大小，将酌情使用传统的桑格或新的高通量测序方法来识别致病基因。我们将使用这些和其他已知的 MHM 致病基因来构建和修改基因和蛋白质的模型生物网络，并在其他患者中测试这些基因和网络作为候选基因或更准确地说是候选网络方法。这些方法需要得到持续积极的受试者招募的支持，因为对精神发育迟滞和自闭症等类似疾病的研究已经受益于我们迄今为止收集的更多受试者。我们需要使用新的高通量测序方法来更有效地测试更大的关键区域，并测试整个基因网络而不是匹配的受试者群体中的单个基因。在表型分析、CNV 分析、模型网络构建和高通量测序的每一步中，我们都需要扩展的生物信息学能力。最后，我们需要测试新基因和网络的生物学功能，以支持我们的基因鉴定研究。我们期望这些研究将立即有助于更准确的诊断和咨询，并且随着时间的推移，将导致针对这些疾病的一部分的特定治疗方法的开发。我们进一步期望中后脑发育的研究将对人类发育障碍具有广泛的意义，为小脑发育与其他类型的发育障碍（例如自闭症、智力低下和癫痫）之间的联系提供令人信服的证据。 公共卫生相关性：脑干和小脑的发育障碍（源自胚胎中脑和后脑）是一类非常重要的疾病，根据 CDC 的数据，每 1000 名居民新生儿中至少有 2.4 人受到影响。真实频率可能要高得多。这一大类疾病与更常见的发育障碍（例如自闭症、智力低下和某些形式的婴儿癫痫）同时发生，并且具有一些相同的原因。我们建议找出几种不同类型的脑干和小脑畸形的原因，这将有助于在短期内提供更准确的诊断和咨询，并在长期内为其中一些疾病提供具体的治疗。