Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course

Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

即便在无明显疾病家族史的病例中，基因组测序（genome sequencing）仍可为临床诊断与管理提供助力。然而，基因组的临床应用尚未实现常规化，部分原因在于临床医师仍在探索如何最佳利用此类信息。作为与医学院人体解剖学课程配套开展的教育性研究实践，我们对1例临床诊断为特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）后离世的患者进行了全基因组测序分析，以探索其应用潜力。参与课程的医学生对该遗体完成了解剖操作与全基因组测序。大体及镜下病理结果更符合非特异性间质性肺炎（nonspecific interstitial pneumonia, NSIP）的纤维化亚型，而非典型的特发性肺纤维化。未检测到可引发孟德尔遗传病（Mendelian disorders）、使患者易患IPF的基因变异。不过，全基因组测序识别出了数个与IPF相关的常见变异，包括位于黏蛋白糖蛋白MUC5B编码基因启动子区域（promoter region）的单核苷酸多态性（single nucleotide polymorphism, SNP）rs35705950。近期研究发现，MUC5B启动子多态性可显著升高IPF的发病风险，但此前尚未见其与NSIP的明确关联报道，也未在全基因组范围内的所有遗传变异背景下评估该位点的疾病风险贡献。我们未在MUC5B邻近的连锁不平衡（linkage disequilibrium, LD）区域内发现其他潜在功能性变异，也未在基因组其他区域找到其他可能的风险相关变异。因此，全基因组测序证实了rs35705950与MUC5B失调及间质性肺疾病的关联。本次创新性实践同时达成了一项独特目标：架起临床教育与基础科学教育之间的桥梁。