The Genetic Basis of Mid-Hindbrain Malformations

描述（由申请人提供）：我们本项目的总体目标是推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，根据CDC的数据，每1000名居民出生中至少有2.4人受到影响。重要的是，这一大类疾病与更常见的发育障碍（如自闭症、智力迟钝和某些形式的婴儿癫痫）共同发生，并且有一些相同的原因。随着这一更新，我们建议扩大我们的工作范围，超越单一表型和基因，专注于描绘最常见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队列，使用SNP微阵列来绘制额外的MHM位点，该微阵列在信息丰富的家族中提供高分辨率的自合子和连锁数据，并检测零星受试者的关键拷贝数变异。致病基因将根据关键区域的大小，使用传统的Sanger或新的高通量测序方法进行鉴定。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学网络，并在其他患者中作为候选基因或更准确地说是候选网络方法测试这些基因和网络。这些方法需要得到正在进行的积极的受试者招募的支持，因为对智力迟钝和自闭症等类似疾病的研究受益于我们迄今收集的更多的受试者。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，而不是在匹配的受试者队列中测试单个基因。在每一步——表型分析、CNV分析、模型网络构建和高通量测序——我们都需要扩展生物信息学能力。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。我们希望这些研究能够立即为更准确的诊断和咨询做出贡献，并随着时间的推移，将导致针对这些疾病子集的特定治疗方法的发展。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（如自闭症、智力迟钝和癫痫）之间的联系提供令人信服的证据。

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.