Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.
Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.
复制标题
DOI：
10.3389/fendo.2015.00113
复制
发表时间：
2015
影响因子：
5.2
通讯作者：
Metherell LA
中科院分区：
文献类型：
--
作者：
Chan LF;Campbell DC;Novoselova TV;Clark AJ;Metherell LA
肾上腺功能不全是一种罕见但可能致命的疾病。在儿童中，病因最常见的是先天性的，近年来，越来越多的致病基因突变被发现，导致无数的综合征，其中一个主要特征是肾上腺功能不全。肾上腺功能不全的演变取决于变异和受影响的特定基因，这意味着快速准确的诊断对于有效治疗患者至关重要。通常的做法是对候选基因进行单独测序，这是一个耗时的过程，并且由于重叠的临床表型而变得复杂。然而，随着全外显子组测序的可用性和成本效益的提高，它有可能成为一种强大的诊断工具。在这里，我们报告了43例诊断为家族性糖皮质激素缺乏症（FGD）的患者的全外显子组测序结果，这些患者在FGD中最常见的突变基因MC2R、MRAP和STAR均为突变阴性。WES在17/43的测序患者中提供了快速的遗传诊断，其余60%的基因缺陷可能在WES未覆盖的内含子/调控区域内，或者可能在代表新病因的基因中。孤立性或家族性糖皮质激素缺乏症的诊断仅在17例患者中有3例得到证实，其他遗传诊断为肾上腺功能低下和增生、aaa和自身免疫性多内分泌病综合征I型，这强调了表型区分PAI疾病的困难以及WES作为实现这一目标的工具的实用性。
Adrenal insufficiency is a rare, but potentially fatal medical condition. In children, the cause is most commonly congenital and in recent years a growing number of causative gene mutations have been identified resulting in a myriad of syndromes that share adrenal insufficiency as one of the main characteristics. The evolution of adrenal insufficiency is dependent on the variant and the particular gene affected, meaning that rapid and accurate diagnosis is imperative for effective treatment of the patient. Common practice is for candidate genes to be sequenced individually, which is a time-consuming process and complicated by overlapping clinical phenotypes. However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool. Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD. WES provided a rapid genetic diagnosis in 17/43 sequenced patients, for the remaining 60% the gene defect may be within intronic/regulatory regions not covered by WES or may be in gene(s) representing novel etiologies. The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.