Novel potentially pathogenic stop codon mutation in the nuclear factor NF-?B p65 subunit (RELA): Discovery of a new player driving inflammation in monogenic Behçet-like disease in the Midwest of Ireland


Fahd Adeeb 1, 2, Emma R. Dorris 3, Austin G. Stack 2, 4, Anthony G. Wilson 3, Alexander D. Fraser 1, 2


1. Department of Rheumatology, University Hospital Limerick, Limerick, Ireland 2. Graduate Entry Medical School, University of Limerick, Limerick, Ireland 3. EULAR Centre of Excellence/UCD Centre for Arthritis Research, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland 4. Department of Nephrology, University Hospital Limerick, Limerick, Ireland


Behçet's Disease (BD) has a multifactorial etiology and susceptibility is influenced by a complex interplay between genetic and environmental components. Familial aggregation in BD has been described among different ethnic populations and there have been reported cases of monogenic conditions with similarity to BD. Better insights and understanding of orphan monogenic defects in inflammatory syndromes carries high clinical impact on the affected patients and "at risk" family members and will hopefully reshape the landscape in managing this subset of BD patients through early recognition, identification of characteristics pattern, risk prediction, choice of treatment and discovery of different novel therapies.


The primary goal of this study was to identify novel genetic mutation(s) in a BD family using whole exome sequencing (WES).


WES were performed on a complex Caucasian Irish pedigree composed of eight family members that include 2 half sisters with BD, both presented with similar phenotypic picture of orogenital ulcerations and skin pustulosis without evidence of uveitis. One of the two proband also had a sister who was subsequently diagnosed with neuromyelitis optica (NMO) while the remaining family members remained healthy and were asymptomatic.


A novel potentially pathogenic stop codon mutation in the nuclear factor NF-κB p65 subunit (RELA) was present in all 3 affected subjects as well as their father. The WES data suggests p65 haploinsufficiency and a dominant mode of inheritance with incomplete penetrance (Figure 1). Activation of the transcriptional regulator NF-κB is a critical step in inflammation and is widely implicated in inflammatory syndromes including in BD. Cytokines that are stimulated by NF-κB, such as IL-1β, TNF-α and IL-6, can also directly activate the NF-κB pathway, thus establishing a positive autoregulatory loop that can amplify the inflammatory response and increase the duration of chronic inflammation. The mutation at the stop codon may potentially have caused uncontrolled inflammation resulting phenotypic characteristics similar to BD.


This study provides novel evidence for the pathogenic stop codon mutation in the nuclear factor NF-κB p65 subunit (RELA) as a potential driver of inflammation in monogenic Behçet-like disease.