Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization

• Published in: Journal of rheumatology Vol. 44; no. 11; pp. 1667 - 1673
• Main Authors: Lasigliè, Denise, Mensa-Vilaro, Anna, Ferrera, Denise, Caorsi, Roberta, Penco, Federica, Santamaria, Giuseppe, Di Duca, Marco, Amico, Giulia, Nakagawa, Kenji, Antonini, Francesca, Tommasini, Alberto, Consolini, Rita, Insalaco, Antonella, Cattalini, Marco, Obici, Laura, Gallizzi, Romina, Santarelli, Francesca, Del Zotto, Genny, Severino, Mariasavina, Rubartelli, Anna, Ravazzolo, Roberto, Martini, Alberto, Ceccherini, Isabella, Nishikomori, Ryuta, Gattorno, Marco, Arostegui, Juan I, Borghini, Silvia
• Format: Journal Article
• Language: English
• Published: Canada 01-11-2017
• Subjects: Brain - diagnostic imaging; Child; Child, Preschool; Cryopyrin-Associated Periodic Syndromes - diagnostic imaging; Cryopyrin-Associated Periodic Syndromes - genetics; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Italy; Magnetic Resonance Imaging; Male; Mosaicism; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; White Matter - diagnostic imaging; PEDIATRIC RHEUMATIC DISEASES; GENETIC STUDIES; NEUROLOGIC MANIFESTATIONS; INFLAMMATION
• ISSN: 0315-162X; 1499-2752
• DOI: 10.3899/jrheum.170041

To evaluate the rate of somatic
mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS).
The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the
gene yielded negative results. Patients' DNA were subjected to amplicon-based
deep sequencing.
Low-level somatic
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).
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.
The allele frequency of somatic
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.