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 t...

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Autores: Bonet, Núria, Pesqué, David, Giménez Arnau, Anna Maria, Laayouni, Hafid, 1968-, Fornas Carreño, Oscar, Aróstegui Gorospe, Juan Ignacio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/71790
Acceso en línea:http://hdl.handle.net/10230/71790
http://dx.doi.org/10.1007/s10875-025-01922-x
Access Level:acceso abierto
Palabra clave:Autoinflammatory diseases
Inflammasome
NLRP3 gene
Mosaicism
Interleukin-1
Interleukin-1 inhibitors
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spelling Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism Bonet, Núria Pesqué, David Giménez Arnau, Anna Maria Laayouni, Hafid, 1968- Fornas Carreño, Oscar Aróstegui Gorospe, Juan Ignacio Autoinflammatory diseases Inflammasome NLRP3 gene Mosaicism Interleukin-1 Interleukin-1 inhibitors 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. 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 Innovación (MCIN) | Agencia Estatal de Investigación (AEI) | https://doi.org/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 Unión Europea Next Generation EU | Mecanismo para la Recuperación y la Resiliencia (MRR) | Plan de Recuperación, Transformación y Resiliencia (PRTR). • 2021SGR01093 | Agència de Gestió d’Ajuts Universitaris i de Recerca | Generalitat de Catalunya (FC). • 21897/PI/22 (PP) and 21214/FPI/19 (LH-N) | Fundación Séneca, Región de Murcia, Spain. Springer http://hdl.handle.net/10230/71790 http://dx.doi.org/10.1007/s10875-025-01922-x
title Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
spellingShingle Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
Bonet, Núria
Autoinflammatory diseases
Inflammasome
NLRP3 gene
Mosaicism
Interleukin-1
Interleukin-1 inhibitors
title_short Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
title_full Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
title_fullStr Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
title_full_unstemmed Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
title_sort Novel insights into the clinical features, genetic spectrum and clonal evolution of patients carrying NLRP3 mosaicism
author Bonet, Núria
author_facet Bonet, Núria
Pesqué, David
Giménez Arnau, Anna Maria
Laayouni, Hafid, 1968-
Fornas Carreño, Oscar
Aróstegui Gorospe, Juan Ignacio
author_role author
author2 Pesqué, David
Giménez Arnau, Anna Maria
Laayouni, Hafid, 1968-
Fornas Carreño, Oscar
Aróstegui Gorospe, Juan Ignacio
author2_role author
author
author
author
author
topic Autoinflammatory diseases
Inflammasome
NLRP3 gene
Mosaicism
Interleukin-1
Interleukin-1 inhibitors
topic_facet Autoinflammatory diseases
Inflammasome
NLRP3 gene
Mosaicism
Interleukin-1
Interleukin-1 inhibitors
description 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.
publishDate 2025
format article
status_str publishedVersion
url http://hdl.handle.net/10230/71790
http://dx.doi.org/10.1007/s10875-025-01922-x
eu_rights_str_mv openAccess
publisher Springer
institution Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
collection Recercat. Dipósit de la Recerca de Catalunya
reponame_str Recercat. Dipósit de la Recerca de Catalunya
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
_version_ 1878439451098611712
publishDateSort 2025
author_browse Aróstegui Gorospe, Juan Ignacio
Bonet, Núria
Fornas Carreño, Oscar
Giménez Arnau, Anna Maria
Laayouni, Hafid, 1968-
Pesqué, David
publisherStr Springer
score 6,924472

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