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）是一种常见的遗传性微缺失综合征，儿童期神经发育异常。在成年期/青春期晚期，精神病的高风险（25-40%）已被确定。早期神经发育异常与晚年精神病之间的关系尚不清楚。由于精神分裂症被认为是一种神经发育障碍，对22q11DS儿童的神经发育和遗传异常的研究将加强对这一弱势群体以及一般人群中导致精神分裂症的轨迹的理解。我们的假设是，22q11DS儿童中最易患精神病的子集可能有：1)神经认知明显且日益恶化的异常；2)额叶、颞叶、顶叶、小脑和胼胝体明显且进行性脑形态异常；3)22q11.2区域内的半合子基因型与其他22q11DS患者不同。在研究结束时，这些孩子出现前驱症状和精神障碍的几率会增加。我们建议对70名患有22q11 DS的非精神病儿童和70名对照组进行神经心理学和神经解剖学变化的纵向研究，并对半合子22q11间隔进行基因型分析。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。我们也会检查前驱症状和精神障碍。2)利用磁共振图像（MRI）进行纵向脑形态计量学分析，量化胼胝体、额叶、颞叶、顶叶和小脑。3)22q11.2区域关键缺失区对应遗传区间的基因型特异性单核苷酸多态性（snp）。作为一个探索性目标，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，并将预测将有前驱症状和精神诊断率升高的子集。摘要：我们将研究22q11 DS儿童的学习障碍、大脑结构和22q11.2区域遗传变异之间的联系，以了解在这种严重精神疾病中起作用的因素。22q11 DS是一种具有精神分裂症高风险的遗传疾病。

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.