Connecting Rare Mutations to Common Pathways

研究项目、项目总结 智力和发育障碍(IDDS)对社会造成严重的情感和经济损失，影响 据估计，美国每6名儿童中就有1名。开发有效的治疗干预措施来治疗IDD是一项具有挑战性的工作 这是一个问题，因为大量的环境和遗传风险因素导致了这些疾病。的确， 已经在700多个基因中发现了与缺碘相关的遗传变异，但每个变异只存在于 少数患者，我们对这些变异如何导致疾病的了解有限。这 高度的遗传异质性和缺乏机械性的洞察力阻碍了开发有效 治疗IDD的疗法。如果单个突变可以通过共享的分子路径进行分组，那么靶向 这些途径可能在较大的患者亚群中有效。我们提案的总体目标是发展 一个将读出IDD的基因组、转录和神经元表型特征的平台 揭示被缺碘相关突变扰乱的常见途径的基因。

Research Project, Project Summary Intellectual and developmental disabilities (IDDs) exact a heavy emotional and financial toll on society, affecting an estimated 1 in 6 children in the US. Developing effective therapeutic interventions to treat IDD is a challenging problem because a large number of environmental and genetic risk factors contribute to these diseases. Indeed, IDD-associated genetic variants have been identified in more than 700 genes, but each variant is present in only a small number of patients, and our understanding of how these variants contribute to the disease is limited. This high degree of genetic heterogeneity and lack of mechanistic insights confound efforts to develop effective therapies to treat IDD. If individual mutations can be grouped by shared molecular pathways, then targeting these pathways may be efficacious in large subsets of patients. The overall goal of our proposal is to develop CRANIUM, a platform that will read out the genomic, transcriptional, and neuronal phenotypic signatures of IDD genes to reveal common pathways disrupted by IDD-associated mutations.