Biomarkers for Psychosis in Velocardiofacial Syndrome

描述（由申请人提供）：由染色体22q11.2上的微缺失引起的速度心面综合征（VCFS），影响1：4000个体，与先天性异常、神经认知缺陷以及高达30%的患有该综合征的成人精神分裂症（SZ）相关。我们只是开始确定预测SZ n个体患有这种遗传疾病的因素。在本申请中，我们建议继续我们于2001年2月开始的VCFS精神病危险因素的纵向研究。在过去的5年中，我们收集了广泛的神经解剖，认知和精神病学的数据在两个时间点83个青年VCFS，他们的33个未受影响的兄弟姐妹和38个社区控制。这些数据使我们能够开始绘制VCFS儿童的认知、精神和神经解剖学发展轨迹，并确定这些因素中哪些因素可预测时间2时精神功能不良。然而，我们样本中的年轻人刚刚达到他们最容易发生SZ的年龄。因此，我们必须继续跟踪这一队列，以确定与SZ发病相关的神经解剖学和神经心理学因素，并可能预测SZ的发病。拟议项目的目标是通过第三阶段的数据收集，扩大我们对这一大样本的调查，这将跨越年龄范围（15-21岁），在此期间，青年VCFS变得容易受到SZ的发病。我们建议应用先进的计算工具来分析特定大脑区域的皮质厚度和皮质形态，我们发现这些区域在VCFS青年中发生了改变，并且可能与精神功能不良有关。然后，我们将研究基因型，脑容量，皮质表面形态/厚度和神经认知功能对精神病结果的影响。我们的具体目标是：1）绘制患有VCFS的青少年的神经解剖学、神经认知和精神轨迹;以确定2）特定脑体积、皮质表面形态和皮质厚度、3）神经心理功能和4）精神障碍的发育轨迹与时间3的SZ的病前或阳性症状相关的程度;和5）确定Val 158 Met COMT多态性中的等位基因变异是否预测在时间3的SZ的发病前或阳性症状。VCFS中的高SZ率构成了家庭和社会的重大公共卫生问题。确定那些因素，使青年与VCFS在SZ的风险最高，将产生积极影响的早期，预防性干预和治疗精神障碍的儿童和青年与VCFS，从而减少其对家庭和社会的损失。

DESCRIPTION (provided by applicant): Velocardiofacial syndrome (VCFS), caused by a microdeletion on chromosome 22q11.2 and affecting 1:4000 individuals, is associated with congenital anomalies, neurocognitive deficits, and, in up to 30% of adults with this syndrome, schizophrenia (SZ). We are only beginning to identify the factors that predict SZ n individuals with this genetic disorder. In this application, we are proposing to continue our longitudinal study of risk factors for psychosis in VCFS that we began in February of 2001. During the past 5 years, we have collected extensive neuroanatomic, cognitive, and psychiatric data at two time points on 83 youth with VCFS, 33 of their unaffected siblings and 38 community controls. These data have permitted us to begin to map the trajectory of cognitive, psychiatric and neuroanatomic development in children with VCFS, and to determine which of these factors predict poor psychiatric function at Time 2. However, the youth in our sample are just reaching the age at which they are most vulnerable to the onset of SZ. Accordingly, it is critical that we continue follow this cohort in order to identify the neuroanatomic and neuropsychological factors that are associated with, and may be predictive of, the onset of SZ. The goal of the proposed project is to extend our investigation of this large sample through a third phase of data collection, which will span the age range (15-21 years) during which youth with VCFS become vulnerable to the onset of SZ. We are proposing to apply advanced computational tools to analyze the cortical thickness and cortical morphology of the specific brain regions that we have found are altered in youth with VCFS and that may be associated with poor psychiatric function. We will then examine the effect of genotype, brain volumes, cortical surface morphology / thickness and neurocognitive function on psychiatric outcome. Our specific aims are: 1) to map the neuroanatomic, neurocognitive and psychiatric trajectory in youth with VCFS; to determine the extent to which the developmental trajectories of 2) specific brain volumes, cortical surface morphology and cortical thickness, 3) neuropsychological function, and 4) psychiatric disorders are associated with either premorbid or positive symptoms of SZ at Time 3; and 5) to determine whether allelic variation in the Val158Met COMT polymorphism predicts either premorbid or positive symptoms of SZ at Time 3. The high rate of SZ in VCFS constitutes a significant public health concern for both families and society. Identifying those factors that place youth with VCFS at the highest risk for SZ will impact positively on the early, preventative intervention and treatment of psychiatrically impaired children and youth with VCFS, thus reducing its toll on families and society.