研究背景： 威斯康辛医学院及儿童医院的科学家们联合完成了医学史上的一项创举：他们为一名3岁的小患者作外显子组基因测序（whole exome sequencing），找到该未知疾病的基因突变。该研究小组不仅对突变进行了诊断，更提出了脐带血移植的治疗方法，阻止了病情的发展。相关论文发表于最新的《医药遗传学》（Genetics in Medicine）在线版上。

小男孩15个月大时即发病，遭受了不下100次手术，但却仍不能摆脱病痛的折磨。他的肠道持续肿胀化脓，所有的医生都说从未见过这种怪病。最终专家们决定，从基因角度挖掘病因。医生解释说，通过详尽的诊断，学者们发现男孩儿的免疫系统显示出大量的反常，但并没有指向某一种特殊的疾病。于是，他们决定给小患者做外显子组测序。

经过3个月的分析，学者们确定了某个基因上一种独特的突变，他们认为，正是这个突变造成了未知的肠道疾病，属于更广义的X连锁凋亡抑制蛋白缺失（XIAP deficiency）的一种。今年6月，研究小组选取匹配的干细胞，对小患者施以脐带血移植手术。5个月后，小男孩从医院返回家中，并能正常进食。

技术方法：外显子组测序

研究意义：本研究向临床医生推出了一种新的治疗手段：使用基因测序作为未知疾病的诊断工具，也许在不远的将来，基因测序有望拓展成为一种常规治疗——诊断工具。

参考文献： Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.

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