Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism
Por:
Bonet N, Mascaro JM Jr, Hurtado-Navarro L, Angosto-Bazarra D, Callejas-Rubio JL, Clemente D, Souto A, Lima O, Palmou-Fontana N, Baselga E, Jiménez-Treviño S, Remesal A, Andreu-Barasoain M, Fernandez-Dominguez L, Riera-Monroig J, Aparicio M, Garcia-Herrero J, Pesqué 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 JMG, de la Fuente EG, Iglesias-Jimenez E, Gomez-Roman J, Vázquez-Triñanes C, Lopez-Robledillo JC, Ortego-Centeno N, Giménez-Arnau AM, Campistol JM, Laayouni H, de Landazuri IO, Yagüe-Ribes J, Gonzalez-Roca E, Mensa-Vilaro A, Fornas O, Ramos E, Pelegrin P, Casals F and Arostegui-Gorospe JI
Publicada:
30 sep 2025
Ahead of Print:
30 sep 2025
Resumen:
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.
Filiaciones:
Bonet N:
Genomics Core Facility, Universitat Pompeu Fabra, Barcelona, Spain
Mascaro JM Jr:
Department of Dermatology, Hospital Clínic, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Hurtado-Navarro L:
Biomedical Research Institute of Murcia, University of Murcia, Murcia, Spain
Angosto-Bazarra D:
Biomedical Research Institute of Murcia, University of Murcia, Murcia, Spain
Callejas-Rubio JL:
Department of Internal Medicine, Hospital Clinico Universitario San Cecilio, Granada, Spain
Clemente D:
Department of Pediatric Rheumatology, Hospital Universitario Niño Jesús, Madrid, Spain
Souto A:
Department of Rheumatology, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
Lima O:
Department of Internal Medicine, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
Palmou-Fontana N:
Department of Rheumatology, Hospital Universitario Marques de Valdecilla, Santander, Spain
Baselga E:
Department of Dermatology, Hospital Sant Joan de Déu, Barcelona, Spain
Jiménez-Treviño S:
Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain
Remesal A:
Department of Pediatric Rheumatology, Hospital Universitario La Paz, Madrid, Spain
Andreu-Barasoain M:
Department of Dermatology, Hospital Fundación Alcorcón, Alcorcón, Spain
Fernandez-Dominguez L:
Department of Rheumatology, Hospital Santa María Nai, Ourense, Spain
Riera-Monroig J:
Department of Dermatology, Hospital Clínic, Barcelona, Spain
Aparicio M:
Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Garcia-Herrero J:
Department of Immunology, Complejo Asistencial Universitario de Leon, Leon, Spain
Pesqué D:
Department of Dermatology, Hospital del Mar Research Institute, Barcelona, Spain
Universitat Autònoma de Barcelona, Barcelona, Spain
Sanchez-Calvin MT:
Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain
Lezana-Rosales JM:
Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain
Correyero-Plaza M:
Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain
Garcia-Villalba J:
Biomedical Research Institute of Murcia, University of Murcia, Murcia, Spain
Bolaño V:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Peiro S:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Diaz M:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Vlagea A:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Lorca D:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Fabregat V:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Anton MC:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Plaza S:
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Gonzalez-Granado LI:
Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain
Postigo C:
Department of Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain
de Morales JMG:
Department of Immunology, Complejo Asistencial Universitario de Leon, Leon, Spain
de la Fuente EG:
Department of Dermatology, Hospital Universitario Ramon y Cajal, Madrid, Spain
Iglesias-Jimenez E:
Department of Pediatric Rheumatology, Hospital Sant Joan de Deu, Barcelona, Spain
Gomez-Roman J:
Department of Pathology, Hospital Universitario Marques de Valdecilla, Santander, Spain
Vázquez-Triñanes C:
Department of Internal Medicine, Complejo Hospitalario Universitario de Vigo, Vigo, Spain
Lopez-Robledillo JC:
Department of Pediatric Rheumatology, Hospital Universitario Niño Jesús, Madrid, Spain
Ortego-Centeno N:
Department of Medicine, University of Granada, Granada, Spain
Giménez-Arnau AM:
Department of Dermatology, Hospital del Mar Research Institute, Barcelona, Spain
Universitat Pompeu Fabra, Barcelona, Spain
Campistol JM:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Department of Nephrology, Hospital Clínic, Barcelona, Spain
Laayouni H:
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Barcelona Beta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
de Landazuri IO:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Yagüe-Ribes J:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Gonzalez-Roca E:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Mensa-Vilaro A:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Fornas O:
Flow Cytometry Unit, Universitat Pompeu Fabra, Barcelona, Spain
Ramos E:
Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain
Pelegrin P:
Biomedical Research Institute of Murcia, University of Murcia, Murcia, Spain
:
Department of Genetics, Microbiology and Statistics, Universitat of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Arostegui-Gorospe JI:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Department of Immunology (esc 4-pl 0), Hospital Clínic, Villarroel 170, Barcelona, 08036, Spain
Green Submitted, hybrid
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