Clinical Features, Outcomes of Treatments, Inflammasome Function and Longitudinal Clonal Dynamics intoNLRP3Mosaicism: Evidence from the Largest Cryopyrin-associated Periodic Syndromes Cohort to Date
Authors: Bonet Nuria , Mascaro Jose M. , Hurtado-Navarro Laura , Angosto-Bazarra Diego , Callejas-Rubio Jose Luis , Clemente Daniel , Souto Alejandro , Lima Olalla , Palmou-Fontana Natalia , Baselga Eulalia , Jiménez-Treviño Santiago , Remesal Agustin , Andreu-Barasoain Marta , Fernandez-Dominguez Luis , Riera-Monroig Josep , Aparicio Maria , Garcia-Herrero Juan , Pesqué David , Sanchez-Calvin Maria Teresa , Lezana-Rosales Jose Miguel , Correyero-Plaza Maria , Garcia-Villalba Julio , Bolaño Victor , Peiro Sara , Diaz Mar , Vlagea Alexandru , Lorca Daniel , Fabregat Virginia , Anton Maria Carmen , Plaza Susana , Gonzalez-Granado Luis Ignacio , Postigo Concepción , Garcia-Ruiz de Morales Jose Maria , Gómez de la Fuente Enrique , Iglesias Estibaliz , Gomez-Roman Javier , Vázquez-Triñanes Caritina , Lopez-Robledillo Juan Carlos , Ortego-Centeno Norberto , Giménez-Arnau Ana María , Campistol Josep M. , Laayouni Hafid , Ortiz de Landazuri Iñaki , Yagüe Jordi , Gonzalez-Roca Eva , Mensa-Vilaro Anna , Fornas Oscar , Ramos Eduardo , Pelegrin Pablo , Casals Ferran , Arostegui Juan I. 
Published: December 2024

Objective

NLRP3mosaicism 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 withNLRP3mosaicism 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 vitroanalyses determined the functional consequences of detected variants.

Results

Seventeen individuals withNLRP3mosaicism 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 germlineNLRP3variants. The overrepresentation ofNLRP3mosaicism 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.

Key Messages

What is already known about this subject?

Cryopyrin-associated periodic syndromes (CAPS) is a dominantly-inherited autoinflammatory disease with three different phenotypes of increasing severity across a continuous spectrum.

The disease is a consequence of monoallelic, gain-of-functionNLRP3variants leading to a constitutive hyperactivation of the NLRP3-inflammasome, with the subsequent IL-1β overproduction.

Recent investigations have established the key role ofNLRP3mosaicism in the pathogenesis of CAPS. However, the number of individuals withNLRP3mosaicism reported to date is small, and the data on the long-term behavior of the disease at clinical and biological levels are scarce.

What does this study add?

We have assembled the largest cohort of individuals withNLRP3mosaicism reported to date to obtain novel evidence that strengthens the understanding of this syndrome.

The clinical manifestations, the results of analytical tests, and the outcomes of treatments in patients withNLRP3mosaicism were in line with previous results collected from patients with germlineNLRP3variants.

We have detected a previously unidentified overrepresentation of late-onset forms among patients withNLRP3mosaicism.

Genetic evidence supports for a large mutational diversity among individuals withNLRP3mosaicism. Despite the fact that, theoretically, any amino acid residue in the protein may be involved in mosaicism, the regions spanning the amino acid residues 300-310 and 560-570 concentrate the larger proportion of post-zygotic variants.

Additional experiments confirmed the two main patterns of mosaicism distribution (myeloid-restricted vs extended) and that the degree of mosaicism remains stable in most patients but can also change over time.

How might this impact on clinical practice?

Considering that genetic analyses represent the unique way to establish a CAPS diagnosis, the data presented here strongly suggest for an adequate analysis of the sequence reads of theNLRP3gene in candidate patients, which should include differential analyses for either germline and post-zygotic variants.

The overrepresentation of late-onset forms among patients withNLRP3mosaicism should be taken into consideration by clinicians treating adult patients in the differential diagnosis of inflammatory diseases starting during adulthood.

The evidence presented here support periodic evaluation of circulatingNLRP3mosaicism to evaluate the disease behavior at biological level over time.