Characterization of a Mendelian Form of Psychosis in a Population Isolate

描述（由申请人提供）：廉价的全外显子组和全基因组测序的最新进展开辟了识别影响常见复杂疾病的罕见变异的前景。虽然每个人只携带少数个体，但高渗透性的罕见变异可能共同解释很大一部分疾病风险。这样的变异可能是单个家庭独有的，即使在大型病例/对照样本中也难以识别。然而，对极端家族中罕见变异的研究有可能为常见疾病的生物学基础提供开创性的见解。例如，患有罕见形式的高胆固醇血症的家庭教会了我们很多关于心脏病生物学的知识。精神分裂症（SCZ）是一种遗传性精神疾病，具有很高的发病率和死亡率。识别导致精神病风险的基因是SCZ的一个决定性特征，应该提供关于SCZ病理生理学的关键信息。我们已经确定了一个大家庭，由于高度渗透的创始人突变，它具有潜在的孟德尔式单基因精神病的所有特征。在这个家庭中，至少有36个人患有精神病（通过亲自诊断访谈证实），他们是一对单身夫妇的孙子或曾孙。此外，这个家庭来自哥斯达黎加偏远地区的一个与世隔绝的人群，在系谱中有已知的血缘关系。有趣的是，也有迹象表明免疫系统参与到受影响的家庭成员中。本研究的目的是利用外显子组测序来确定该家族中导致精神病的突变，并表征其影响，包括外显子率，神经认知和神经领域的可变表达性，以及潜在的免疫系统参与。我们还将评估哥斯达黎加SCZ患者中该突变的流行程度，并测试该基因的其他突变是否会影响美国白种人、西班牙裔和非裔美国人病例和对照的SCZ风险。

DESCRIPTION (provided by applicant): Recent advances in inexpensive whole exome and whole genome sequencing have opened up the prospect of identifying rare variants influencing common, complex diseases. Though only carried in a few individuals each, highly penetrant rare variants may collectively explain a large portion of disease risk. Such variants might be private to a single family, making them difficult to identify even in large case/control samples. However, the study of rare variants in extreme families has the potential to provide groundbreaking insights into the biology underlying common disease. For example, families with rare forms of hypercholesterolemia taught us much about the biology of heart disease. Schizophrenia (SCZ) is a heritable mental illness associated with substantial morbidity and mortality. Identifying genes that contribute to risk of psychosis, a defining feature of SCZ, shoul provide critical information regarding SCZ pathophysiology. We have identified a large extended family that has all the hallmarks of a potentially Mendelian, monogenic form of psychosis due to a highly penetrant founder mutation. There are at least 36 individuals with psychosis (verified by in person diagnostic interviews) in this family who are grandchildren or great grandchildren of a single couple. Additionally, the family comes from an isolated population in a remote location in Costa Rica and there is known consanguinity in the pedigree. Interestingly, there are also indications of immune system involvement in affected members of the family. The goal of this study is to utilize exome sequencing to identify the mutation responsible for psychosis in this family and characterize its effects, including penetrance, variable expressivity in the neurocognitive and neurological domains, and potential immune system involvement. We will also assess the prevalence of the mutation in individuals with SCZ in Costa Rica and test whether other mutations in this gene may influence SCZ risk in a sample of US Caucasian, Hispanic, and African American cases and controls.