Cushing's Disease Whole Exome Sequencing Study

我们目前正在分析全外显子组测序（WES）数据，并进行适当的随访，以确定与库欣病（CD）和相关异常身体特征相关的重要遗传因素。 最终目标是确定导致CD的遗传变异或变异。 CD是一种脑垂体产生不适当的高水平促肾上腺皮质激素（ACTH）的疾病。 ACTH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的垂体瘤引起的。 CD是一种严重的疾病。 需要手术切除肿瘤。 肿瘤有时会复发，在这种情况下，需要放射或药物治疗，但并不总是成功的。 由于高皮质醇水平，CD会导致广泛的问题。 这些包括糖尿病、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）是鉴定与医学状况相关的重要遗传变异的有力工具。 它是一种确定基因组中所有被翻译成蛋白质的区域（外显子）的遗传密码（序列）的有效方法。 外显子约占DNA的1%，因此测序外显子提供了大量的信息，其成本低于测序整个基因组。 本研究评价了在NICHD就诊的确诊CD的儿科老年患者。 那些有组织病理学证实的疾病与DNA，激素文件的疾病和完整的临床数据是潜在的情况下。 已经完成了将病例中发现的变异与大对照人群进行比较的分析。 此外，正在检查外显子中拷贝数变异的数据，以确定它们是否在库欣病中起作用。 我们已经在一个大的单一队列中显示了多个生殖系和体细胞变异对库欣病的贡献。在所有这些案件中占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子的研究没有发现任何强有力的遗传修饰因子。 我们已经确定了新的遗传协会与异位垂体后叶和确认以前的协会。

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.