Risk Factors for Psychosis in Chromosome 22q11 Deletion Syndrome

描述(申请人提供)：染色体22q11.2缺失综合征(22q11DS)是一种常见的遗传微缺失综合征，在儿童时期就有神经发育异常。在成年期/青春期后期，精神病的风险非常高(25%-40%)。早期神经发育异常与晚年精神病之间的关系尚不清楚。对22q11DS儿童神经发育和遗传异常的研究将增强对这一脆弱群体以及普通人群导致精神分裂症的轨迹的理解，因为精神分裂症被认为是一种神经发育障碍。我们的假设是，最容易患精神病的22q11DS儿童的子集将具有：1)明显的和恶化的神经认知异常；2)额叶、颞叶和顶叶、小脑和胼胝体的明显和进行性的形态异常；3)22q11.2区域内与其他22q11DS儿童不同的半合子基因。这些儿童在研究结束时会有更高的前驱症状和精神障碍的比率。我们对70名患有22q11 DS的非精神病儿童和70名对照受试者进行了一项神经心理学和神经解剖学改变的纵向研究，并对22q11.2半合子区间进行了基因分析。其目的是：1)对神经认知进行纵向评估，包括持续注意力、执行功能和言语工作记忆。我们还将测试前驱症状和精神障碍。2)在核磁共振图像(MRI)上进行纵向脑形态计量学分析，以定量检测在22q11.2区域关键缺失区域对应的遗传区间中的基因特异性单核苷酸多态(SNPs)。作为一个探索性的目标，我们将在22q11DS患者中创建单倍型(连锁基因型)。这些发现将相互关联，并将预测具有更高的前驱症状和精神诊断比率的子集。Lay摘要：我们将研究患有22q11 DS儿童的学习障碍、大脑结构和遗传变异之间的联系，以了解在这种严重精神疾病中发挥作用的因素。22q11 DS是一种高风险精神分裂症的遗传疾病。

DESCRIPTION (provided by applicant): Chromosome 22q11.2 Deletion Syndrome (22q11DS) is a common genetic microdeletion syndrome, with neurodevelopmental abnormalities in childhood. A remarkably high-risk of psychoses (25-40%) has been identified in adulthood/late adolescence. The relationship between the early neurodevelopmental abnormalities and psychoses in later life is unclear. The study of the neurodevelopmental and genetic abnormalities in children with 22q11DS would enhance the understanding of the trajectory that leads to schizophrenia in this vulnerable group as well as in the general population, since schizophrenia is thought to be a neurodevelopmental disorder. Our hypotheses are that the subset of 22q11DS children that is most vulnerable to psychosis would have: 1) pronounced and worsening abnormalities of neurocognition 2) pronounced and progressive morphological brain abnormalities of the frontal, temporal and parietal lobes, cerebellum and the corpus callosum 3) hemizygous genotypes within the 22q11.2 region that will be distinct from the rest with 22q11DS. These children would have an increased rate of prodromal symptoms and psychiatric disorders at the end of the study. We propose a longitudinal study of the neuropsychological and neuroanatomical changes, and genotype analysis of the hemizygous 22q11.2 interval in a cohort of 70 nonpsychotic children with 22q11 DS and 70 control participants. The aims are to: 1) Conduct a longitudinal assessment of neurocognition, including sustained attention, executive function and verbal working memory. We will also test for prodromal symptoms and psychiatric disorders. 2) Perform longitudinal brain morphometric analyses on magnetic resonance images (MRI) to quantify the corpus callosum, frontal, temporal, and parietal lobes and the cerebellum 3) Genotype specific single nucleotide polymorphisms (SNPs) in the genetic interval corresponding to the critical deleted area of the 22q11.2 region. An an exploratory aim, we will create haplotypes (linked genotypes) in the 22q11DS patients. These findings will be correlated with one another and will be predictive of the subset that will have elevated rates of prodromal symptoms and psychiatric diagnoses. Lay Summary: We will study the links between learning disabilities, brain structure and hereditary variants in the 22q11.2 region in children with 22q11 DS, a genetic condition with a high risk of schizophrenia, to understand the factors that play a role in this severe mental illness.