Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism

NLRP3 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.

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Publication Details

Journal
Journal of Clinical Immunology
Published
2025-09-30
DOI
https://doi.org/10.1007/s10875-025-01922-x
Citations
2
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
1.61
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article

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism

Maria Carmen Anton, Iñaki Ortiz de Landazuri, María Teresa Sánchez‐Calvín, Pablo Pelegrı́n et al.
2 citations
Journal of Clinical Immunology
Inflammasome and immune disorders
1.61
article

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism

Maria Carmen Anton, Iñaki Ortiz de Landazuri, María Teresa Sánchez‐Calvín, Pablo Pelegrı́n, Julio García-Villalba, Salvador Peiró, José Luís Callejas-Rubio, Anna Mensa‐Vilaró, José M. Mascaró, José María García-Ruiz de Morales, Juan Carlos López-Robledillo, Virginia Fabregat, Eulàlia Baselga, E. Iglesias, Marta Andreu‐Barasoain, L. Fernández-Dominguez, Josep Maria Campistol, Olalla Lima, Diego Angosto-Bazarra, Maria Correyero-Plaza, Ferrán Casals, Núria Bonet, Jordi Yagüe, Daniel Clemente, Michael Joseph Diaz, Norberto Ortego‐Centeno, M. Aparicio, Ana Maria Giménez‐Arnau, David Pesqué, Natalia Palmou‐Fontana, Javier Gómez‐Román, José Miguel Lezana Rosales, C. Postigo, Juan I. Aróstegui, Hafid Laayouni, Santiago Jiménez-Treviño, Laura Hurtado‐Navarro, Luis Ignacio González‐Granado, C. Vázquez-Triñanes, Òscar Fornas, Alexandru Vlagea, Josep Riera‐Monroig, Eva González‐Roca, Victor Bolaño, Eduardo Ramos, Enrique Gómez de la Fuente, Alejandro Souto, Agustín Remesal, Susana Plaza, Juan Garcia-Herrero, Daniel Lorca
article en
2 citations

Abstract

NLRP3 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.

Journal of Clinical ImmunologyVol. 45(1)
Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), Universitat Pompeu Fabra (ES), Universidad de Granada (ES), Hospital Universitario La Paz (ES), Instituto de Salud Carlos III (ES), University Hospital Complex Of Vigo (ES), Hospital Universitari de Santa Maria (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario Fundación Alcorcón (ES), Hospital Universitario 12 De Octubre (ES), Pasqual Maragall Foundation (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Infantil Universitario Niño Jesús (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Clínic de Barcelona (ES), Hospital Del Mar (ES), Hospital Universitario Central de Asturias (ES), Hospital Universitari Germans Trias i Pujol (ES), Complejo Hospitalario de Pontevedra (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación de Enfermedades Raras (ES), Hospital Universitario Ramón y Cajal (ES), Complejo Asistencial Universitario de Palencia (ES), Complejo Hospitalario de Ourense (ES), Institut de Recerca Sant Joan de Déu, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona (ES), Universidad de Murcia (ES)
Openalex Percentile: Top 15%
Inflammasome and immune disorders
1.61
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