Cushing's Disease Whole Exome Sequencing Study

我们目前正在分析整个外显子组测序(WES)数据，并进行适当的跟进，以确定与库欣病(CD)相关的重要遗传因素和相关的异常身体特征。最终目标是确定导致CD的一个或多个遗传变异。 慢性萎缩性脑病是一种脑下垂体产生不适当的高水平促肾上腺皮质激素(ACTH)的情况。促肾上腺皮质激素刺激肾上腺产生过量的皮质醇，导致临床疾病。CD是由分泌ACTH的脑垂体瘤引起的。CD是一种严重的疾病。它需要手术来移除肿瘤。肿瘤有时会复发，在这种情况下，需要放射治疗或药物治疗，但并不总是有效。由于皮质醇水平较高，镉可引起广泛的问题。这些疾病包括糖尿病、骨折、生长不良和高血压。CD可能是致命的。 全外显子组测序(WES)是识别与疾病相关的重要遗传变异的有力工具。这是一种有效的方法来确定基因组中所有被翻译成蛋白质的区域的遗传密码(序列)，即外显子。外显子约占DNA的1%，因此测序外显子提供了大量的信息，成本低于测序整个基因组。 这项研究对NICHD确诊为CD的老年儿童患者进行了评估。那些有组织病理学证实的疾病并伴有DNA、疾病的激素记录和完整的临床数据的人是潜在的病例。 对在大量对照人群中发现的变异进行了分析比较。此外，正在对这些数据进行外显子拷贝数变异的检查，以确定它们是否在库欣病中发挥作用。 我们已经在一个大的单一队列中展示了多个生殖系和体细胞变异对库欣病的贡献。在所有这些案例中占20%。我们对下丘脑-垂体-肾上腺轴恢复时间的可能遗传预测因素的研究没有发现任何强大的遗传修饰因素。 我们发现了与异位后垂体腺的新的遗传关联，并确认了以前的关联。

We are currently analyzing whole exome sequencing (WES) data with appropriate follow up to identify important genetic factors associated with Cushing's disease (CD) and related abnormal physical features. The ultimate goal is to identify a genetic variant or variants that cause CD. CD is a condition in which the pituitary gland produces inappropriately high levels of adrenocorticotropic hormone (ACTH). The ACTH stimulates the adrenal gland to produce excess cortisol, leading to clinical disease. CD is caused by ACTH secreting pituitary tumors. CD is a serious condition. It requires surgery to remove the tumor. The tumors sometimes recur in which case radiation or medical therapy is required which is not always successful. CD can cause a wide range of problems due to the high cortisol levels. These include diabetes, fractures, poor growth, and hypertension. CD can be fatal. Whole exome sequencing (WES) is a powerful tool for identifying important genetic variants associated with medical conditions. It is an efficient method of determining the genetic code (sequence) of all the regions in the genome that are translated into protein, the exons. The exons constitute about 1% of DNA, thus sequencing exons provides a large amount of information at a lower cost than sequencing the entire genome. Pediatric aged patients seen at NICHD with a confirmed diagnosis of CD are evaluated for this study. Those who have histopathologically confirmed disease in conjunction with DNA, hormonal documentation of the disease and complete clinical data are potential cases. Analysis comparing variants found in the cases with large control populations has been done. In addition, the data are being examined for copy number variants in the exons to determine if they play a role in Cushing's disease. We have shown the contributions of multiple germline and somatic variants to Cushing disease in a large single cohort. In all these account for 20% of cases. Our investigation of possible genetic predictors of time to recovery of the hypothalamic-pituitary-adrenal axis did not uncover any strong genetic modifiers. We have identified new genetic associations with ectopic posterior pituitary and confirmed previous associations.