Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease
Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease
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DOI：
10.1097/gim.0b013e3182088158
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发表时间：
2011-03-01
影响因子：
8.8
通讯作者：
Dimmock, David P.
中科院分区：
文献类型：
--
作者：
Worthey, Elizabeth A.;Mayer, Alan N.;Dimmock, David P.
目的：我们报告了一名男婴，在15个月大时出现肛周脓肿和直肠炎，进展为透壁性全结肠炎伴结肠皮瘘，与克罗恩病样疾病一致。年龄和严重程度的介绍表明潜在的免疫缺陷，然而，尽管全面的临床评价，我们无法达到明确的诊断，从而限制了临床管理。研究方法：我们试图通过外显子组测序确定致病突变，为临床管理提供必要的额外信息。结果：测序后，我们确定了16，124个变体。随后的分析确定了一种新的，半合子错义突变的X-连锁细胞凋亡抑制基因，取代酪氨酸的高度保守和功能重要的半胱氨酸。X连锁凋亡抑制剂以前与克罗恩病无关，但在促炎反应和通过NOD信号通路的细菌传感中起核心作用。在有执照的临床实验室中通过桑格测序证实了该突变。功能分析表明，增加的敏感性激活诱导的细胞死亡和缺陷的NOD 2配体的反应，与正常的X-连锁的细胞凋亡抑制蛋白功能的细胞凋亡和NOD 2信号转导的损失。结论：根据病史、遗传和功能数据，该儿童被诊断为X连锁细胞凋亡抑制剂缺乏症。基于这一发现，进行了异基因造血祖细胞移植，以防止危及生命的噬血细胞性淋巴组织细胞增生症的发展，与X连锁细胞凋亡抑制剂缺乏症的推荐治疗一致。在移植后>42天，孩子能够进食和饮水，并且没有胃肠道疾病复发，这表明这种突变也导致了胃肠道疾病。这份报告描述了一种新的炎症性肠病病因的鉴定。同样重要的是，它展示了外显子组测序在所有标准诊断都用尽后，在新疾病背景下对个体患者进行分子诊断的能力，并说明了这项技术如何用于临床环境。Genet Med 2011：13（3）：255-262.
Purpose: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management. Methods: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management. Results: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling. Conclusions: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting. Genet Med 2011: 13(3): 255-262.