Identifying Genetic Predictors of Stroke Using Next Generation Sequencing

镰状细胞病最严重的并发症之一是脑血管疾病。 一些患者可能会经历从无症状到轻微症状的小范围缺血事件。 其他患者在年轻时可能会经历大脑大动脉的完全闭塞。这些患者 可迅速发展为烟雾病和脑血流灌注不足。如果没有慢性输血治疗或 骨髓移植，患有严重脑血管疾病的患者患相关疾病的风险很高 到生命的第三个十年时死亡。识别中风的危险因素将允许及早 脑动脉闭塞前的预防性干预。 。在过去的几年里，已经有了几个关于全基因组和全外显子组的开创性出版物。 测序应用了患者-父母三联体来确定新生儿疾病的遗传基础。我们将应用一个 类似的方法来定义潜在的遗传修饰因素，以预测风险并提供更好的理解 镰状细胞病儿童早期发病的大脑大动脉疾病。我们已经确定并 收集了8个家庭的DNA样本，这些家庭有一个以上的孩子患有镰状细胞疾病，但只有 一名儿童出现大面积脑动脉闭塞。而不是患者-父母三合一，我们将使用兄弟作为 附加控制。从理论上讲，没有镰状细胞疾病的父母可能携带突变或 预测镰状细胞相关脑血管疾病的单核苷酸多态。但是，在 无镰状细胞表型，无卒中表型。 这项试验的另一个目标是发展生物信息学和计算生物学专业知识，以纯净 涉及下一代测序应用的其他项目。为了让这项技术 可用于其他项目，我们将开发和验证质量保证驱动的生物信息学 输油管道。这将是这一试点项目的后半部分的重点。我们将使用在以下位置获得的数据 为镰状细胞病患者开发和验证管道。这条管道和方法将是 可扩展以适应更大规模的未来研究。

One of the life-threatening and most severe complications of sickle cell disease is cerebral vascular disease. Some patients may experience small ischemic events that range from asymptomatic to mildly symptomatic. Other patients may experience complete occlusion of a large cerebral artery at a young age. These patient may quickly develop moya moya and deficient cerebral perfusion. Without chronic transfusion therapy or a bone marrow transplant, patients with significant cerebral vascular disease have a high risk for diseaserelated mortality by the third decade of life. Identification of risk factors for stroke will permit early preventative interventions prior to cerebral artery occlusion. . In the past few years, there have been several seminal publications of whole genome and whole exome sequencing applied patient-parent triads to define the genetic basis of disease in newborns. We will apply a similar approach to define potential genetic modifiers that predict risk and offer a better understanding of early onset large cerebral artery disease in children with sickle cell disease. We have identified and collected DNA samples on eight families with more than one child affected by sickle cell disease, but only one child with large cerebral artery occlusion. Instead of patient-parent triads, we will use the sibling as an additional control. Theoretically, it is possible for a parent without sickle cell disease to carry a mutation or single nucleotide polymorphism that predicts sickle cell associated cerebral vascular disease. However, in the absence of the sickle cell phenotype, there is no stroke phenotype. Another aim for this pilot is to develop the bioinformatic and computational biology expertise to pursure additional projects involving the application of next generation sequencing. To make this technology available for additional projects, we will develop and validate a quality assurance driven bioinformatics pipeline. This will be the focus of the second half of this pilot project. We will use the data obtained in patients with sickle cell disease to develop and validate the pipeline. This pipeline and approach will be scalable for larger future studies.