Journal: ACR Open Rheumatology
First author: Alexandre Belot
Country of study: France, United Kingdom — international narrative review
CEREMAIA Tenon author: Sophie Georgin-Lavialle
Full reference: Belot A, Tusseau M, Cognard J, Georgin-Lavialle S, Boursier G, Hedrich CM. How (Ultra-)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases. ACR Open Rheumatology. 2025;7(2):e70003.
5 key points
1. Rare mutations in a single gene can cause specific forms of lupus or Behçet syndrome.
2. Studying these rare forms helps explain the immune mechanisms involved in more common diseases.
3. In monogenic lupus, several rare genetic defects interfere with the clearance of cell debris or cause excessive interferon activity, a key driver of inflammation.
4. In Behçet syndrome, some rare variants highlight the major role of the NF-κB pathway, which is involved in immune activation.
5. Better understanding of these genetic abnormalities may support more targeted treatments and more personalized medicine.
Introduction
Inflammatory diseases such as systemic lupus or Behçet syndrome are usually complex and linked to several genetic and environmental factors. However, in a small number of patients, a single rare genetic abnormality may play a major role. This article explains how studying these rare forms can improve our understanding of the more common forms of these diseases.
Methods
This is a narrative review. The authors summarize current knowledge about rare and ultra-rare genetic variants involved in monogenic forms of lupus and Behçet syndrome, with a focus on biological mechanisms and the consequences for research and patient care.
Results
In lupus, several rare genetic abnormalities have highlighted important mechanisms: poor clearance of cell debris, complement defects, abnormal DNA or RNA regulation, excessive type I interferon activity, overactivation of immune pathways such as TLR or JAK/STAT, and loss of immune tolerance. In Behçet syndrome, rare variants in genes such as **TNFAIP3**, **RELA**, or **NFKB1** have shown the central role of another inflammatory pathway called **NF-κB**. Other rarer abnormalities further confirm the diversity of possible disease mechanisms.
Discussion
The article shows that diseases that look similar clinically may actually have different biological causes. This helps improve disease classification, explain early, severe or unusual cases, and identify more precise treatment targets. In practice, genetics may be especially useful in younger patients or in patients with atypical or familial forms.
Conclusion
Studying rare variants is not only important for exceptional cases: it also improves our understanding of more common inflammatory diseases. In the future, this approach may support more accurate diagnosis and treatments that are better tailored to each patient.
