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Case Reports
. 2015 Sep;67(9):2482-6.
doi: 10.1002/art.39190.

Brief Report: Cryopyrin-Associated Periodic Syndrome Caused by a Myeloid-Restricted Somatic NLRP3 Mutation

Qing Zhou  1 , Ivona Aksentijevich  1 , Geryl M Wood  1 , Avram D Walts  2 , Patrycja Hoffmann  1 , Elaine F Remmers  1 , Daniel L Kastner  1 , Amanda K Ombrello  1
Affiliations
Case Reports

Brief Report: Cryopyrin-Associated Periodic Syndrome Caused by a Myeloid-Restricted Somatic NLRP3 Mutation

Qing Zhou et al. Arthritis Rheumatol. 2015 Sep.

Abstract

Objective: To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional Sanger DNA sequencing.

Methods: We performed whole-exome sequencing and targeted deep sequencing using DNA from the patient's whole blood to identify a possible NLRP3 somatic mutation. We then screened for this mutation in subcloned NLRP3 amplicons from fibroblasts, buccal cells, granulocytes, negatively selected monocytes, and T and B lymphocytes and further confirmed the somatic mutation by targeted sequencing of exon 3.

Results: We identified a previously reported CAPS-associated mutation, p.Tyr570Cys, with a mutant allele frequency of 15% based on exome data. Targeted sequencing and subcloning of NLRP3 amplicons confirmed the presence of the somatic mutation in whole blood at a ratio similar to the exome data. The mutant allele frequency was in the range of 13.3-16.8% in monocytes and 15.2-18% in granulocytes. Notably, this mutation was either absent or present at a very low frequency in B and T lymphocytes, in buccal cells, and in the patient's cultured fibroblasts.

Conclusion: Our findings indicate the possibility of myeloid-restricted somatic mosaicism in the pathogenesis of CAPS, underscoring the emerging role of massively parallel sequencing in clinical diagnosis.

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Figures

Figure 1
Figure 1
(A) Sanger sequencing electropherograms of the patient with somatic NLRP3 mosaicism (c.1709A>G, p.Tyr570Cys) from whole blood DNA (upper panel) and in representative subclones (lower panels). Arrows indicate the position of the somatic mutation. The frequency of the somatic mutant allele in whole blood is 10.4% (172 clones with wild type A allele and 20 clones with mutant G allele, respectively). (B) Mapped reads from exome sequencing and targeted sequencing of DNA from whole blood support the presence of the mutation c.1709A>G by Integrative Genomics Viewer. (C) Summary table of the somatic mutation allele frequency and read depth in different cell lineages determined by targeted sequencing.
Figure 2
Figure 2
The schematic diagram shows cell lineage development from hematopoietic and mesenchymal stem cells. The somatic NLRP3 mutation, c.1709A>G, is restricted to monocytes and granulocytes and comparable data from two sequencing techniques suggest that the somatic event likely occurred in myeloid progenitor cells.
See this image and copyright information in PMC

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