Brief Report: Cryopyrin‐Associated Periodic Syndrome Caused by a Myeloid‐Restricted Somatic NLRP3 Mutation. Issue 9 (September 2015)

• Record Type: Journal Article
• Authors: Zhou, Qing; Aksentijevich, Ivona; Wood, Geryl M.; Walts, Avram D.; Hoffmann, Patrycja; Remmers, Elaine F.; Kastner, Daniel L.; Ombrello, Amanda K.
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 9(2015)
• Page Start: 2482
• Page End: 2486
• Publication Date: 2015-09
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39190
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art39190-sec-0001" sec-type="section"> <title>Objective</title> <p>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) <italic>NLRP3</italic> mutations by conventional Sanger DNA sequencing.</p> </sec> <sec id="art39190-sec-0002" sec-type="section"> <title>Methods</title> <p>We performed whole‐exome sequencing and targeted deep sequencing using DNA from the patient's whole blood to identify a possible <italic>NLRP3</italic> somatic mutation. We then screened for this mutation in subcloned <italic>NLRP3</italic> 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.</p> </sec> <sec id="art39190-sec-0003" sec-type="section"> <title>Results</title> <p>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 <italic>NLRP3</italic> 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.</p> </sec> <sec id="art39190-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>