近日，美国艾伯维基因组学研究中心Nizar Smaoui团队揭示了临床队列中的常见疾病-并不总是其看起来的那样。2025年10月23日出版的《新英格兰医学杂志》发表了这项成果。

在诊断为常见病的患者中，罕见病的误诊或漏诊可能导致治疗延误或不适当，从而使罕见病和常见病的管理复杂化。尽管分子诊断技术取得了进步，但在研究和临床试验中，罕见病对常见病诊断的影响尚未得到全面的研究。

研究组使用来自英国生物银行参与者的外显子组和基因组测序数据，一项研究和五项临床试验，这些临床试验涉及最初诊断为多发性硬化症、炎症性肠病或特应性皮炎的患者，以评估通常表现为临床症状与这些常见疾病重叠的单基因罕见疾病的发病率。

研究组发现153名英国生物银行的参与者携带一种罕见的变异，这种变异有助于单基因疾病的分子诊断——1850人中有53人（2.86%）诊断为多发性硬化症，6681人中有75人（1.12%）诊断为炎症性肠病，998人中有25人（2.50%）诊断为特应性皮炎。研究组在两个独立的队列中重复了关于这种罕见的致病变异的发现——一个包括诊断为多发性硬化症的患者，另一个包括诊断为炎症性肠病的患者——他们分别进行了研究和临床试验的基因组测序。通过结合基因组和转录组分析，研究组发现分子诊断可以潜在地阐明对治疗干预反应不足的机制。

研究结果证明了系统基因组测序在理解常见疾病的表型异质性和识别罕见疾病诊断失败方面的价值，并强调了深度分子表型在临床试验和患者护理中的益处。

附：英文原文

Title: Common Diseases in Clinical Cohorts — Not Always What They Seem

Author: Fedik Rahimov, Benjamin M. Jacobs, John S. Lee, Naim A. Mahi, Andrew Blumenfeld, Ammar J. Alsheikh, Ali Abbasi, Mark Reppell, Valerie L. Pivorunas, Haukur J. Siguresson, Stephen Sawcer, Heath Guay, Jeffrey F. Waring, Howard J. Jacob, Nizar Smaoui

Issue&Volume: 2025-10-23

Abstract:

BACKGROUND

Misdiagnosis or underdiagnosis of rare diseases in patients with diagnoses of common diseases can lead to delayed or inappropriate treatments, thereby complicating the management of both rare and common conditions. Despite advances in molecular diagnostic techniques, the effect of rare diseases on the diagnosis of common diseases in research and clinical trials has not been comprehensively investigated.

METHODS

We used exome- and genome-sequencing data from participants in the U.K. Biobank, a research study, and five clinical trials involving patients who had received a primary diagnosis of multiple sclerosis, inflammatory bowel disease, or atopic dermatitis to assess the incidence of monogenic rare diseases that often manifest with clinical symptoms overlapping with those of these common diseases.

RESULTS

We identified 153 U.K. Biobank participants who carried a rare variant that contributes to a molecular diagnosis of a monogenic disorder — 53 of 1850 (2.86%) with a diagnosis of multiple sclerosis, 75 of 6681 (1.12%) with a diagnosis of inflammatory bowel disease, and 25 of 998 (2.50%) with a diagnosis of atopic dermatitis. We replicated the findings regarding such rare disease–causing variants in two independent cohorts — one including patients with a diagnosis of multiple sclerosis, and the other patients with a diagnosis of inflammatory bowel disease — who had undergone genome sequencing for research and for clinical trials, respectively. By combining genome and transcriptome analyses, we showed that molecular diagnosis can potentially elucidate mechanisms of inadequate response to therapeutic intervention.

CONCLUSIONS

Our study shows the value of systematic genome sequencing in understanding the phenotypic heterogeneity of common diseases and identifying failure to diagnose rare diseases and highlights the benefits of deep molecular phenotyping in clinical trials and patient care.

DOI: NJ202510233931609

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2405459