Background/Purpose: A20 is a critical anti-inflammatory protein encoded by the TNFAIP3 (tumor necrosis factor alpha-induced protein 3) gene. A20 negatively regulates multiple anti-inflammatory pathways including TNF-NFκB signaling, inflammasome activation, and interferon (IFN) signaling. Inactivating mutations in TNFAIP3 cause the monogenic disease A20 haploinsufficiency (HA20). HA20 is classically considered as a form of atypical Behcet’s disease. However, recent data suggest that HA20 causes diverse clinical signs and symptoms of autoinflammation, autoimmunity, lymphoproliferation, and humoral immunodeficiency. These diverse clinical presentations have only been characterized through meta-analyses of reported cases, leading to potential ascertainment bias. We therefore aimed to better characterize the clinical presentations of patients with truncating mutations in TNFAIP3 who were systematically analyzed through the University of Pittsburgh-NIH HA20 cohort (n = 50).

Methods: Patients and families with TNFAIP3 truncating or missense mutations were identified through patient referral. Patients underwent Invitae Primary Immunodeficiency (PID) panel sequencing at >50x coverage. Families underwent comprehensive evaluation to determine clinical course and inheritance patterns.

Results: 41 pLOF patients (age range 3-74, 56% male) and 9 missense patients (age range 3-87, 56% male) were included in this cohort.

Conclusion: HA20 is classically characterized as atypical Bechet’s disease, yet these patients experience widely diverse clinical presentations. This diversity is observed when comparing those with pLOF and missense mutations as well as within these respective patient populations. In addition, HA20 patients are at increased risk for life-threatening complications such as autoimmune hepatitis and vasculitis. Ascertainment bias can limit diagnosis if genetic testing is only performed on subjects with atypical Behcet’s disease, leading to missed opportunities for targeted therapy. Future studies are needed to better characterize the molecular drivers of HA20 phenotypes in patients with pLOF and missense TNFAIP3 variants to guide appropriate screenings and treatment for these patient populations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tnfaip3-loss-of-function-and-missense-mutations-demonstrate-clinically-diverse-presentations-a-multi-center-cohort-experience/