Bonet, NúriaPesqué, DavidGiménez Arnau, Anna MariaLaayouni, Hafid, 1968-Fornas Carreño, OscarAróstegui Gorospe, Juan Ignacio2025-11-062025-11-062025Bonet N, Mascaro JM, Hurtado-Navarro L, Angosto-Bazarra D, Callejas-Rubio JL, Clemente D, Souto A, Lima O, Palmou-Fontana N, Baselga E, Jimenez-Treviño S, Remesal A, Andreu-Barasoain M, Fernandez-Dominguez L, Riera-Monroig J, Aparicio M, Garcia-Herrero J, Pesque D, Sanchez-Calvin MT, Lezana-Rosales JM, Correyero-Plaza M, Garcia-Villalba J, Bolaño V, Peiro S, Diaz M, Vlagea A, Lorca D, Fabregat V, Anton MC, Plaza S, Gonzalez-Granado LI, Postigo C, de Morales JMGR, de la Fuente EG, Iglesias E, Gomez-Roman J, Vazquez-Triñanes C, Lopez-Robledillo JC, Ortego-Centeno N, Gimenez-Arnau AM, Campistol JM, Laayouni H, de Landazuri IO, Yague J, Gonzalez-Roca E, Mensa-Vilaro A, Fornas O, Ramos E, Pelegrin P, Casals F, Arostegui JI. Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism. J Clin Immunol. 2025 Sep 30;45(1):134. DOI: 10.1007/s10875-025-01922-x0271-9142http://hdl.handle.net/10230/71790NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of 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. 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.application/pdfeng© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.info:eu-repo/semantics/article2025-11-06http://dx.doi.org/10.1007/s10875-025-01922-xAutoinflammatory diseasesInflammasomeNLRP3 geneMosaicismInterleukin-1Interleukin-1 inhibitorsinfo:eu-repo/semantics/openAccess