RT Journal Article
SR Electronic
T1 Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP jrheum.170041
DO 10.3899/jrheum.170041
A1 Denise Lasigliè
A1 Anna Mensa-Vilaro
A1 Denise Ferrera
A1 Roberta Caorsi
A1 Federica Penco
A1 Giuseppe Santamaria
A1 Marco Di Duca
A1 Giulia Amico
A1 Kenji Nakagawa
A1 Francesca Antonini
A1 Alberto Tommasini
A1 Rita Consolini
A1 Antonella Insalaco
A1 Marco Cattalini
A1 Laura Obici
A1 Romina Gallizzi
A1 Francesca Santarelli
A1 Genny del Zotto
A1 Mariasavina Severino
A1 Anna Rubartelli
A1 Roberto Ravazzolo
A1 Alberto Martini
A1 Isabella Ceccherini
A1 Ryuta Nishikomori
A1 Marco Gattorno
A1 Juan I.  Arostegui
A1 Silvia Borghini
YR 2017
UL http://www.jrheum.org/content/early/2017/09/11/jrheum.170041.abstract
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.