期刊
JOURNAL OF RHEUMATOLOGY
卷 44, 期 11, 页码 1667-1673出版社
J RHEUMATOL PUBL CO
DOI: 10.3899/jrheum.170041
关键词
GENETIC STUDIES; PEDIATRIC RHEUMATIC DISEASES; INFLAMMATION; NEUROLOGIC MANIFESTATIONS
类别
资金
- Giovani Ricercatori-Ricerca Finalizzata [GR-2010-2315933]
- Italian Ministry of Health
- Ricerca Corrente
- Ricerca Telethon [GGP14144]
- CERCA Programme/Generalitat de Catalunya
- Spanish Ministry of Economy and Competitiveness [SAF2015-68472-C2-1-R]
- Fondo Europeo de Desarrollo Regional
- Instituto de Salud Carlos III/Transnational Research Projects on Rare Diseases [AC15/00027]
- Grants-in-Aid for Scientific Research [15H04876] Funding Source: KAKEN
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.
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