Association Between Pathogenic Variants in Nlrp12 and Autoinflammatory Disease: A Comprehensive Systematic Review Publisher



N Vatandoost NASIMEH ; S Biglari SAJJAD ; T Ranjbarnejad TAYEBEH ; H Vahidnezhad HASSAN ; S Jafarpour SIMA ; M Abdolvand MOHAMMAD ; M Salehi MANSOUR ; R Sherkat ROYA
Source: International Journal of Immunogenetics Published:2025

Abstract

Systemic auto-inflammatory diseases (SAID) are rare inherited conditions characterized by dysregulation of the immune system, which leads to recurrent episodes of fever and systemic inflammation. Recent studies have identified pathogenic variants in the nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12) gene as potential contributors to autoinflammatory syndromes. Therefore, evaluating NLRP12 gene variants is crucial for the differential diagnosis of patients presenting symptoms associated with autoinflammatory diseases, specifically those known as NLRP12-associated autoinflammatory disease (NLRP12-AID). This study aims to identify causal variants in the NLRP12 gene encoding for NLRP12 and to discuss its pathogenesis, clinical features, and emerging treatment approaches. We used specific keywords for a systematic literature review via EMBASE, Scopus, ScienceDirect, Web of Science, and PubMed. Out of 874 articles, 27 met the inclusion criteria. To our knowledge, 103 patients with NLRP12 variants have been reported in the literature. All 60 variants in the NLRP12 coding gene were identified, including 49 classified as variants of uncertain significance (VUS), pathogenic, and likely pathogenic. The results show that the mean age of onset was 13.18 years. Fever was reported as the main symptom in 90% of cases of NLRP12-AID. Other symptoms, such as rash and urticaria, occurred in 59% of cases, myalgia and arthralgia in 39% of cases, arthritis in less than 20%, and abdominal pain/diarrhea in 50% of patients. In summary, the clinical features of NLRP12-AID are diverse and impact several tissues, particularly the musculoskeletal and gastrointestinal systems. In addition to familial cold autoinflammatory syndrome (FCAS) symptoms. Owing to its variable expression and incomplete penetrance, NLRP12-AID is often misdiagnosed. Therefore, we believe that patients with a syndrome of undifferentiated recurrent fever should also undergo genetic evaluation for NLRP12. © 2025 Elsevier B.V., All rights reserved.