Cryopyrin-associated periodic syndromes in Italian Patients: Evaluation of the rate of somatic NLRP3 mosaicism and phenotypic characterization

Denise Lasigliè, Anna Mensa-Vilaro, Denise Ferrera, Roberta Caorsi, Federica Penco, Giuseppe Santamaria, Marco Di Duca, Giulia Amico, Kenji Nakagawa, Francesca Antonini, Alberto Tommasini, Rita Consolini, Antonella Insalaco, Marco Cattalini, Laura Obici, Romina Gallizzi, Francesca Santarelli, Genny Del Zotto, Mariasavina Severino, Anna RubartelliRoberto Ravazzolo, Alberto Martini, Isabella Ceccherini, Ryuta Nishikomori, Marco Gattorno, Juan I. Arostegui, Silvia Borghini

Research output: Contribution to journalArticlepeer-review


Objective: To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS). Methods: The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients' DNA were subjected to amplicon-based NLRP3 deep sequencing. Results: Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging. Conclusion: The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated. The Journal of Rheumatology

Original languageEnglish
Pages (from-to)1667-1673
Number of pages7
JournalJournal of Rheumatology
Issue number11
Publication statusPublished - Nov 1 2017


  • Genetic studies
  • Neurologic manifestations
  • Pediatric rheumatic diseases inflammation

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology


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