Structural and Functional Characteristics of XYY - Relationship to ASD

 描述（由申请人提供）：该提案解决了对儿童健康非常重要的两个挑战：定义自闭症谱系障碍（ASD）的遗传病因和建立ASD的临床病理生理机制。孤独症在美国很常见，影响约1%的人口，并且在病因、发病机制和临床表现方面具有异质性。ASD的一个已知的遗传风险因素是男性性染色体疾病，47，XYY综合征（XYY）。大约三分之一的男性XYY患者符合ASD的诊断标准，XYY在自闭症队列中的代表性显着过高;但这种显着的关联尚未得到充分研究。与ASD的4：1男性优势相结合，XYY中ASD风险增加表明涉及性连锁基因（即XYY中Y染色体基因拷贝数增加导致与大脑发育和功能相关的Y连锁基因过度表达，从而增加ASD风险）。这项建议的总体目标是：1）更好地了解Y染色体在ASD中的特殊作用，考虑到男性的优势和性连锁基因的可能参与，2）在这个相对遗传同质的自闭症模型中，提高对ASD的神经解剖学和神经生理学相关性的理解3）为了启发我们对可能推广到更广泛的自闭症谱系的趋同病理生理机制的理解，和4）描述XYY男孩行为症状的神经相关性，从而为未来的靶向治疗和干预提供依据。 为了实现这些目标，我们将在四组（每组20名）年龄匹配（6-16岁）的男孩中对比ASD的临床，行为和神经生理学标志物：XYY伴ASD（XYY+ASD），XYY不伴ASD（XYY-ASD），ASD-特发性（ASD-I）和典型发育（TD）对照。现有的充分表征的数据集将用于ASD-I和TD队列。将从80名患有XYY的男孩中获得认知和行为表型，以产生40名（20名XYY+ASD / 20名XYY-ASD）适合成像的受试者。目的1和2旨在通过比较四组中ASD的临床/行为标志物（目的1）和局部皮质神经生理学（脑磁图）标志物（目的2），确定XYY+ASD和ASD-I人群之间的共性以及XYY人群中ASD表型的特异性（XYY+ASD vs XYY-ASD）。目标3将通过关键神经递质GABA和谷氨酸的神经化学磁共振波谱和定量扩散MRI探索神经生理学措施的潜在机制。目的4检查临床/行为表型标记物与神经生理学、神经化学和神经影像学测量之间的相互作用，并将证明XYY+ASD中的ASD与ASD-I共享神经生物学基础。这项创新研究利用了独特的XYY队列（Ross博士）的ASD特征系统化，广泛的ASD-I神经影像学专业知识（Roberts博士），多学科团队的引人注目的协同作用，多模式数据收集和复杂的多变量分析。

 DESCRIPTION (provided by applicant): This proposal addresses two challenges of great importance to child health: defining genetic etiologies of autism spectrum disorders (ASD) and establishing clinical-pathophysiological mechanisms in ASD. Autism is common in the US, affecting ~1% of the population, and is heterogeneous with regard to etiology, pathogenesis, and clinical presentation. A known, genetic risk factor for ASD is the male sex chromosome disorder, 47,XYY syndrome (XYY). Approximately one third of males with XYY satisfy diagnostic criteria for ASD, and XYY is significantly overrepresented in autism cohorts; yet this significant association is understudied. Coupled with the 4:1 male predominance for ASD, the increased risk for ASD in XYY suggests the involvement of sex-linked genes (i.e. increased Y chromosome gene copy number in XYY leads to over- expression of Y-linked genes related to brain development and function, thereby increasing ASD risk). The overarching goals of this proposal are to 1) better understand the particular role of the Y-chromosome in ASD, given the male preponderance and likely involvement of sex-linked genes, 2) to improve understanding of the neuroanatomic and neurophysiologic correlates of ASD in this relatively genetically homogeneous model of autism 3) to enlighten our understanding of convergent pathophysiological mechanisms that may generalize to the broader autism spectrum, and 4) to characterize the neural correlates of behavioral symptoms in boys with XYY, leading towards future targeted treatments and interventions. To accomplish these goals, we will contrast the clinical, behavioral and neurophysiological markers of ASD in four groups (20 per group) of age-matched (6-16 yrs) boys: XYY with ASD (XYY+ASD), XYY without ASD (XYY-ASD), ASD-Idiopathic (ASD-I) and typically developing (TD) controls. An existing well-characterized dataset will be used for ASD-I and TD cohorts. Cognitive and behavioral phenotypes will be obtained from 80 boys with XYY to yield 40 (20 XYY+ASD / 20 XYY-ASD) subjects suitable for imaging. Aims 1 and 2 seek to establish commonalities between the XYY+ASD and ASD-I populations as well as specificities of the ASD phenotype within the XYY population (XYY+ASD vs XYY-ASD) by comparing clinical/behavioral markers of ASD (in Aim 1) and local cortical neurophysiologic (magnetoencephalography) markers (in Aim 2) in the four groups. The mechanisms underlying the neurophysiologic measures will be probed in Aim 3, via the neuro- chemical magnetic resonance spectroscopy of key neurotransmitters GABA and glutamate and quantitative diffusion MRI. Aim 4 examines interactions between clinical/behavioral phenotypic markers and neurophys- iological, neurochemical and neuroimaging measures and will demonstrate that ASD in XYY+ASD shares a neurobiological basis with ASD-I. This innovative study takes advantage of the methodical ASD characteriza- tion of the unique XYY cohort (Dr. Ross), extensive ASD-I neuroimaging expertise (Dr. Roberts), compelling synergies of the multidisciplinary team, multi-modal data collection, and sophisticated multivariate analysis.