Submission Details

Autosomal dominant

04/17/2019

The NLRC4 gene is located on chromosome 2 at 2p22.3 and encodes the NLR family CARD domain containing 4 protein. As a key component of the NLRC4 inflammasome, this protein plays an important role in innate immune responses. NLRC4 oligomerization triggers inflammasome assembly and activation, which leads to the activation of caspase-1, production of cytokines such as IL-1β and IL18, and inflammatory cell death, or pyroptosis. NLRC4 was first reported in relation to autosomal dominant NCRL4 related autoinflammatory syndrome in 2014 (25217960: Romberg et al. 201; 25217959: Canna et al. 2014). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. At least five missense variants have been identified in a heterozygous state in six affected cases (25217960: Romberg et al. 2014; 25217959: Canna et al. 2014; 25385754: Kitamura et al. 2014; 27203668: Volker-Touw et al. 2017; 29778503: Moghaddas et al. 2018). In four affected individuals NLRC4 variants occurred de novo, in two families the NLRC4 variant segregated with disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Data examining the impact of pathogenic variants on NLRC4 function, provide evidence for a gain of function mechanism of disease (25217960: Romberg et al. 2014; 25217959: Canna et al. 2014; 25385754: Kitamura et al. 2014). The gene-disease relationship is also supported by a knock-in mouse model which recapitulates the human phenotype (25385754: Kitamura et al. 2014). In summary, NLRC4 is definitively associated with autosomal dominant NCRL4 related autoinflammatory syndrome. Lumping and splitting considerations: OMIM 616115: Familial cold autoinflammatory syndrome 4; OMIM 616050:Autoinflammation with infantile enterocolitis. According to the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern and the above disorders were ‘lumped’ into the term NLRC4-associated autoinflammatory disease. Duncan and Canna (2018; PMID 29247997) describe the spectrum of NLRC4-associated autoinflammatory diseases and highlight that not all patients with NLRC4 inflammasomopathy develop macrophage activation syndrome (MAS) or enterocolitis. All variants described to date in association with this spectrum of disorders have been heterozygous gain-of-function variants, indicating no difference in inheritance pattern or disease mechanism. Although a small number of patients have been described, the possibility of genotype/phenotype correlation based on variant location has been proposed.

25217960 25217959 29778503 27203668 29247997 25385754