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研究背景： 威斯康辛醫(yī)學(xué)院及兒童醫(yī)院的科學(xué)家們聯(lián)合完成了醫(yī)學(xué)史上的一項(xiàng)創(chuàng)舉：他們?yōu)橐幻?歲的小患者作外顯子組基因測序（whole exome sequencing），找到該未知疾病的基因突變。該研究小組不僅對突變進(jìn)行了診斷，更提出了臍帶血移植的治療方法，阻止了病情的發(fā)展。相關(guān)論文發(fā)表于最新的《醫(yī)藥遺傳學(xué)》（Genetics in Medicine）在線版上。 小男孩15個(gè)月大時(shí)即發(fā)病，遭受了不下100次手術(shù)，但卻仍不能擺脫病痛的折磨。他的腸道持續(xù)腫脹化膿，所有的醫(yī)生都說從未見過這種怪病。最終專家們決定，從基因角度挖掘病因。醫(yī)生解釋說，通過詳盡的診斷，學(xué)者們發(fā)現(xiàn)男孩兒的免疫系統(tǒng)顯示出大量的反常，但并沒有指向某一種特殊的疾病。于是，他們決定給小患者做外顯子組測序。 經(jīng)過3個(gè)月的分析，學(xué)者們確定了某個(gè)基因上一種獨(dú)特的突變，他們認(rèn)為，正是這個(gè)突變造成了未知的腸道疾病，屬于更廣義的X連鎖凋亡抑制蛋白缺失（XIAP deficiency）的一種。今年6月，研究小組選取匹配的干細(xì)胞，對小患者施以臍帶血移植手術(shù)。5個(gè)月后，小男孩從醫(yī)院返回家中，并能正常進(jìn)食。 技術(shù)方法：外顯子組測序 研究意義：本研究向臨床醫(yī)生推出了一種新的治療手段：使用基因測序作為未知疾病的診斷工具，也許在不遠(yuǎn)的將來，基因測序有望拓展成為一種常規(guī)治療——診斷工具。 參考文獻(xiàn)： 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 |
