Autoinflammatory diseases (AIDs) are inherited disorders of innate immunity that usually start during childhood. However, several studies have recently reported an increasing number of patients with AID starting in adulthood.
This study was undertaken to characterize the cause underlying a patient with late-onset uncharacterized AID.
Genetic studies were performed using Sanger sequencing and next-generation sequencing (NGS) methods. In silico, in vitro and ex vivo analyses were performed to determine the functional consequences of the detected variant.
We studied a 57 years-old woman who started at the age of 47 years with recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies and systemic inflammation, which were relatively well controlled with anti-IL-1 drugs. NGS analyses did not detect germline variants in any of the known AID-associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2-4%) compatible with gene mosaicism. Structural modeling analyses suggest that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its trend to oligomerize and activate the NLRC4-inflammasome, with a subsequent IL-18 overproduction.
We have identified the post-zygotic p.Ser171Phe NLRC4 variant as a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support for the first time its gain-of-function behavior consistent with previously reported NLRC4 pathogenic variants. These novel evidences should be considered in the diagnostic workup of patients with uncharacterized AID starting during adulthood.