ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders

摘要：胼胝体是人脑中最大的纤维束，连接并整合了这两者 大脑半球胼胝体（ACC）的发生率为1/2，000， 综合征和常见的神经发育障碍（NDD），包括癫痫，智力障碍（ID）， 自闭症谱系障碍（ASD）、脑瘫和精神分裂症。总的来说，这些影响了5%以上的 这是一个重大的公共卫生问题。最近的证据，包括我们的团队，点 遗传病因学的重要性我们的整个外显子组的努力，在这个赠款的初步提交确定了70 ACC基因达到全基因组意义，其中许多是强有力的新候选基因 需要进一步验证根据人口估计，我们预计，数百个额外的基因， 为了发现ACC遗传学的全部范围并利用模型系统取得进展，我们 汇集了一个杰出的研究团队，为ACC的生物学做出了重大贡献。 我们将共同推进基因发现，并解决CC开发的关键问题。为此，我们将： 目的1：确定ACC和NDD的新的从头遗传原因。为此，我们将招募，获得临床 为来自UCSF和合作者的1000多个ACC三重奏提供数据和进行WES。我们还将获得遗传 来自美国两个最大的商业外显子组测序实验室的2000多个trios的信息， GeneDx和Invitae。我们还将利用MatchMaker利用社区的基因发现工作， 与IRC 5（国际胼胝体和大脑连接研究联盟： www.IRC5.org），PI的共同创立。这些共同努力将确保强大的新基因发现。 目标#2：发现ACC的遗传原因，超越生殖系从头编码变异。除了基因 根据上述发现，我们假设许多ACC病例是由复杂基因组区域的突变引起的。 我们将首先集中在阿博迪综合征，一个高度复杂但独特的脑畸形疾病。我们将 从受影响的脑组织（6个在手）和其他组织进行短读深WGS，与 Broad Mendelian基因组中心，进行长读序测序以解析复杂的基因组结构 和其它难以测序的区域。我们还将利用相同的工作流程来解决基因发现问题， 类似的表型统一条件，特别是集中在多重病例。 目标#3：参与ACC候选基因的功能确认和分析。在我们目前的 在生物周期中，我们对C12 ORF 57的研究取得了重大进展。在这份提案中，我们将推进 这是直接的，1。研究C12 ORF 57和CAMKIV的蛋白质相互作用网络。我们亦会研究 CAMKIV与转录因子CREB和AMPA受体调节相关的信号通路， 兴奋性神经传递的关键神经递质受体。这项工作可能对以下方面产生重要影响： 癫痫和可能的认知障碍的治疗策略。

Abstract: The corpus callosum – the largest fiber tract in the human brain, connects and integrates the two cerebral hemispheres. Agenesis of the corpus callosum (ACC) with an incidence of 1 in 2,000 occurs in rare syndromes and in common neurodevelopmental disorders (NDD) including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), cerebral palsy and schizophrenia. Collectively these affect more than 5% of the population and constitute a major public health concern. Recent evidence including from our team, points to the importance of genetic etiologies. Our whole exome efforts in this grant’s initial submission identified 70 ACC genes that reached genome-wide significance, of which many of which are strong novel candidate genes that need further validation. Based on population estimates, we expect that several hundred additional genes will cause ACC. To discover the full range of ACC genetics and to make progress using model systems, we bring together an outstanding investigative team that has made significant contributions to the biology of ACC. Together we will advance gene discovery, and tackle key questions on CC development. To do so we will: Aim 1: Identify novel de novo genetic causes of ACC and NDD. To do so, we will recruit, obtain clinical data and conduct WES for 1000+ ACC trios from UCSF and collaborators. We will also receive genetic information from 2000+ trios from the two largest commercial exome sequencing laboratories in the US, GeneDx and Invitae. We will also leverage the community’s gene discovery efforts using MatchMaker, and work with the IRC5 (international research consortium for the corpus callosum and cerebral connectivity: www.IRC5.org), which the PI’s co-founded. These combined efforts will ensure robust novel gene discovery. Aim #2: Discover genetic causes of ACC beyond germline de novo coding variants. In addition to gene discovery above, we hypothesize that many ACC cases are caused by mutations in complex genomic regions. We will initially focus on Aicardi syndrome, a highly complex yet distinctive brain malformation disorder. We will conduct short-read deep WGS from affected brain tissue (6 in hand) and other tissues, collaborating with the Broad Mendelian Genome Center, to perform long-read sequencing to resolve complex genomic architecture and other difficult to sequence regions. We will also utilize the same work flow to tackle gene discovery in similarly phenotypically unified conditions in particular focusing on multiplex cases. Aim #3: Engage in functional confirmation and analysis of ACC candidate genes. During our current cycle, we have made significant progress studying the biology C12ORF57. In this proposal, we will advance this directly, by 1. Studying the protein interaction network for C12ORF57 and CAMKIV. We will also study the signaling pathways that link CAMKIV to the transcription factor CREB and to regulation of AMPA receptors, the key glutamatergic receptors for excitatory neural transmission. This work may have critical implications for treatment strategies in epilepsy and possibly disorders of cognition.