The schizophrenia-associated 3q29 deletion: genetic architecture of behavioral phenotypes

摘要 3q29缺失综合征是由21个基因的1.6Mb缺失引起的。症候群是 与患精神分裂症和认知障碍的风险惊人地增加40倍有关， 自闭症和社会残障率、执行功能缺陷和注意力缺陷的显著流行率 多动障碍(ADHD)、临床上显著的图形运动无力和焦虑的表现 精神错乱。造成这种表型异质性的因素尚不清楚。我们建议 评估200名有3q29缺失的个体，以更好地定义表型表现并识别风险 关键表型的修饰符。特别是，我们试图理解多基因背景和性别是如何 先证者可能会改变精神病、认知障碍、社会功能和其他表型的风险。至 为了方便我们的评估和减弱确定偏差，我们开发了一种远程表型电池， 它不需要前往测试地点。这款远程电池消除了我们参与的障碍 并极大地降低了成本，提高了我们的研究效率。使用经过验证的 表型分析，我们将鉴定200个新的研究对象的3q29缺失，并确定完整的 表型谱、性别相关的表型风险和显著的共病关系。我们还将 与3q29缺失综合征相关的表型亲生父母的疾病负担 背离亲本中的表型，明确3q29缺失的表型异质性范围 综合症。我们将收集我们研究对象的DNA，以直接测试多基因风险对 选定的表型。最后，在与NIMH赞助的基因2精神健康网络的合作下，我们 将3q29缺失综合征的表型谱和风险修饰物与来自&gt；2000个样本进行比较 与神经发育和神经精神障碍相关的其他基因组疾病，包括 22q11.2缺失和复制、16p11缺失和复制、1q21缺失等。在这个结束的时候 项目中，我们将对3q29缺失相关表型进行全面调查，了解 性别和多基因背景如何增加或降低3q29缺失综合征的表型风险， 以及对3q29缺失与罕见遗传疾病的更广泛前景进行比较的欣赏 与发育性大脑障碍有关。这项研究的所有基因和表型数据将被共享 在公开可用的数据库中，包括DBGaP和ndar。

Summary 3q29 deletion syndrome is caused by a typically de novo 1.6 Mb deletion of 21 genes. The syndrome is associated with an astonishing 40-fold increased risk for schizophrenia, as well as cognitive disability, a high rate of autism and social disability, executive function deficits and pronounced prevalence of attention deficit hyperactivity disorder (ADHD), clinically significant graphomotor weakness, and manifestation of anxiety disorders. The factors that contribute to this phenotypic heterogeneity are not understood. We propose to evaluate 200 individuals with the 3q29 deletion, to better define phenotypic manifestations and identify risk modifiers for key phenotypes. In particular, we seek to understand how polygenic background and sex of the proband may modify risk for psychosis, cognitive disability, social functioning, and other phenotypes. To facilitate our evaluation and attenuate ascertainment bias, we have developed a remote phenotyping battery, which does not require travel to a testing site. This remote battery removes barriers to participation for our study subjects and dramatically reduces costs, improving the efficiency of our study. Using this validated phenotyping protocol, we will characterize 200 new study subjects with the 3q29 deletion, and identify the full phenotypic spectrum, sex-dependent phenotypic risks and significant comorbid relationships. We will also phenotype biological parents to contextualize the burden of illness in 3q29 deletion syndrome relative to departure from mid-parental phenotype, and clarify the range of phenotypic heterogeneity in 3q29 deletion syndrome. We will collect DNA from our study subjects, to directly test the contribution of polygenic risk to selected phenotypes. Finally, in a collaboration with the NIMH-sponsored Genes 2 Mental Health Network, we will compare the phenotypic spectrum and risk modifiers of 3q29 deletion syndrome with >2,000 samples from other genomic disorders associated with neurodevelopmental and neuropsychiatric disorders, including 22q11.2 deletion and duplication, 16p11 deletion and duplication, 1q21 deletion, and others. At the end of this project, we will have a comprehensive survey of 3q29 deletion associated phenotypes, an understanding of how sex and polygenic background may increase or attenuate phenotypic risks in 3q29 deletion syndrome, and an appreciation for how the 3q29 deletion compares to the broader landscape of rare genetic disorders associated with developmental brain disorders. All genotype and phenotype data from this study will be shared in publicly-available databases, including dbGaP and NDAR.