| Title: | Common Diseases in Clinical Cohorts - Not Always What They Seem |
| Journal: | The New England Journal of Medicine |
| Published: | 23 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41124632/ |
| DOI: | https://doi.org/10.1056/nejmoa2405459 |
Publication 16666
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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.</p>
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.</p>
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.</p>
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. (Funded by AbbVie and NIHR Cambridge Biomedical Research Centre.).</p>
21 Keywords
- Adult
- Aged
- Clinical Trials as Topic
- Cohort Studies
- Dermatitis, Atopic
- Diagnostic Errors
- Exome Sequencing
- Female
- Gene Expression Profiling
- Humans
- Incidence
- Inflammatory Bowel Diseases
- Male
- Middle Aged
- Molecular Diagnostic Techniques
- Multiple Sclerosis
- Prospective Studies
- Rare Diseases
- UK Biobank
- United Kingdom
- Whole Genome Sequencing
15 Authors
- 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 Sigurðsson
- Stephen Sawcer
- Heath Guay
- Jeffrey F Waring
- Howard J Jacob
- Nizar Smaoui
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health