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First Description of Late‐Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism

2021; Wiley; Volume: 74; Issue: 4 Linguagem: Inglês

10.1002/art.41999

2326-5205

Daniela Ionescu, Alejandro Peñín‐Franch, Anna Mensa‐Vilaró, Paola Castillo, Laura Hurtado‐Navarro, Cristina Molina‐López, Silvia Romero‐Chala, Susana Plaza, Virginia Fabregat, Segundo Buján, Joana Marques, Ferrán Casals, Jordi Yagüe, Baldomero Oliva, Luis Fernández-Pereira, Pablo Pelegrı́n, Juan I. Aróstegui,

Eosinophilic Esophagitis

Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late-onset uncharacterized autoinflammatory disease.Genetics 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-year-old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti-interleukin-1 (anti-IL-1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease-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 suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL-18.Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is 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 findings should be considered in the diagnostic evaluation of patients with adult-onset uncharacterized autoinflammatory disease.