PT - JOURNAL ARTICLE AU - Denise Lasigliè AU - Anna Mensa-Vilaro AU - Denise Ferrera AU - Roberta Caorsi AU - Federica Penco AU - Giuseppe Santamaria AU - Marco Di Duca AU - Giulia Amico AU - Kenji Nakagawa AU - Francesca Antonini AU - Alberto Tommasini AU - Rita Consolini AU - Antonella Insalaco AU - Marco Cattalini AU - Laura Obici AU - Romina Gallizzi AU - Francesca Santarelli AU - Genny del Zotto AU - Mariasavina Severino AU - Anna Rubartelli AU - Roberto Ravazzolo AU - Alberto Martini AU - Isabella Ceccherini AU - Ryuta Nishikomori AU - Marco Gattorno AU - Juan I. Arostegui AU - Silvia Borghini TI - Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization AID - 10.3899/jrheum.170041 DP - 2017 Sep 15 TA - The Journal of Rheumatology PG - jrheum.170041 4099 - http://www.jrheum.org/content/early/2017/09/11/jrheum.170041.short 4100 - http://www.jrheum.org/content/early/2017/09/11/jrheum.170041.full AB - 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.