Low-frequency mosaicism in cryopyrin-associated periodic fever syndrome: mosaicism in systemic autoinflammatory diseases

Abstract Autoinflammatory disease is an ‘inborn error of immunity’, resulting in systemic inflammation. Cryopyrin-associated periodic syndrome (CAPS) is a prototypical autoinflammatory disease caused by gain-of-function mutations in the NLRP3 (NLR family pyrin domain containing 3) gene; these mutati...

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Bibliographic Details
Published in:International immunology 2019-09, Vol.31 (10), p.649-655
Main Authors: Nishikomori, Ryuta, Izawa, Kazushi, Kambe, Naotomo, Ohara, Osamu, Yasumi, Takahiro
Format: Article
Language:English
Subjects:
Cryopyrin-Associated Periodic Syndromes - genetics
Cryopyrin-Associated Periodic Syndromes - immunology
Humans
Inflammasomes - genetics
Inflammasomes - immunology
Mosaicism
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLR Family, Pyrin Domain-Containing 3 Protein - immunology
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Summary:Abstract Autoinflammatory disease is an ‘inborn error of immunity’, resulting in systemic inflammation. Cryopyrin-associated periodic syndrome (CAPS) is a prototypical autoinflammatory disease caused by gain-of-function mutations in the NLRP3 (NLR family pyrin domain containing 3) gene; these mutations activate the NLRP3 inflammasome, resulting in overproduction of IL-1β. The first case of CAPS caused by somatic NLRP3 mosaicism was reported in 2005 after identification of variant small peaks by Sanger sequencing. An international collaborative study revealed that the majority of mutation-negative CAPS cases are due to low-level NLRP3 mosaicism, suggesting that central nervous system involvement in somatic mosaicism patients is milder than in genotype-matched heterozygous patients. Recent advances in next-generation sequencing have expanded the number of NLRP3 somatic mosaicism cases and identified a new entity called ‘late-onset CAPS with myeloid-specific NLRP3 mosaicism’; however, no mosaic-specific clinical features have been identified/confirmed yet. With respect to NLRP3 mosaicism in CAPS, a prospective longitudinal study on the variant genotype, its allele frequency and its tissue distribution (along with a comprehensive clinical phenotype) would provide better understanding of NLRP3 mosaicism, resulting in more appropriate patient care and genetic counseling. Mosaicism in CAPS
ISSN:1460-2377
1460-2377
DOI:10.1093/intimm/dxz047