Objective NLRP3 mosaicism is a well-established mechanism causing cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we have assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. Methods Patients data were collected from their medical charts. Genetic analyses were performed using Sanger and next-generation sequencing. In vitro analyses determined the functional consequences of detected variants. Results Seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Conclusions Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.

The authors have declared no competing interest.

Funding This work has been partially funded by: PID2021-125106OB-C31 (JIA), PID2020-116709RB-I00 (PP), CNS2022-135101 (PP), PID2023-147531OB-I00 (PP), PID2021-125106OB-C32 (FC), RED2022-134511-T (PP, JIA) and PID2021-125106OB-C33 (OF) grants from the Ministerio de Ciencia e Innovacion (MCIN); Agencia Estatal de Investigacion (AEI); 10.13039/501100011033; Fondo Europeo de Desarrollo Regional (FEDER), UE; European Union Next Generation EU/PRTR. AC21_2/00042 (JIA) and IFI22/00031 (JG-V) grants from the Instituto de Salud Carlos III co-funded by Union Europea Next Generation EU; Mecanismo para la Recuperacion y la Resiliencia (MRR); Plan de Recuperacion, Transformacion y Resiliencia (PRTR). 2021SGR01093; Agencia de Gestio Ajuts Universitaris i de Recerca; Generalitat de Catalunya (FC). 21897/PI/22 (PP) and 21214/FPI/19 (LH-N); Fundacion Seneca, Region de Murcia, Spain.

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The Ethical Review Board of Hospital Clinic approved the study (code HCB/2022/0855).

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Data sharing statement The data included in the present work are, by definition, deidentified, and are available upon reasonable request to the corresponding author. Data shall only be made available after approval by the study contributors of a submitted research proposal, with investigator support and after a signed data access agreement.