Myeloid lineage–restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 2; pp. 561 - 564.e4
• Main Authors: de Koning, Heleen D., van Gijn, Mariëlle E., Stoffels, Monique, Jongekrijg, Johanna, Zeeuwen, Patrick L.J.M., Elferink, Martin G., Nijman, Isaac J., Jansen, Patrick A.M., Neveling, Kornelia, van der Meer, Jos W.M., Schalkwijk, Joost, Simon, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015; Elsevier Limited
• Subjects: Allergy and Immunology; Carrier Proteins - genetics; Deoxyribonucleic acid; DNA; Genes; Genotype & phenotype; High-Throughput Nucleotide Sequencing; Humans; Lymphocytes; Mosaicism; Mutation; Myeloid Cells - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein; Patients; Schnitzler Syndrome - diagnosis; Schnitzler Syndrome - genetics
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.07.050

No NLRP3 genetic variants were found in any of the analyzed cell types derived from 2 patients with Schnitzler syndrome without NLRP3 variants in whole blood (Table I). Because we have previously demonstrated that IL-1β is a pivotal mediator of the clinical signs of Schnitzler syndrome,2,5 we proceeded to investigate the functional consequences of the NLRP3 mosaic mutations on IL-1β and IL-6 production in PBMCs (see the Methods section in this article's Online Repository at www.jacionline.org). The identified variant is considered a benign polymorphism.E5 In patient 7 we detected a known missense mutation in the NACHT domain of the NLRP3 gene (c.1569C>G; p.F523L), which was previously reported as disease causing in 2 infants with NOMID/CINCA, a severe early-onset form of CAPS.E6Canonical SS, Variants located in a canonical splice site; Coding+SS, all variants located either in exonic regions or canonical splice sites; Indels, Insertions or deletions; Known variant (HGMD), variants described as pathogenic in the Human Gene Mutation Database (www.hgmd.org); Missense (phyloP >2.5),E4 highly conserved missense variants with a phyloP >2.5; Nonsense, nonsense variants; Nonsynonymous, variants leading to an amino acid change; Not seen before (in house), variants that have not been detected in 672 in-house sequenced whole exomes; Patient, patient who has undergone whole-exome sequencing; Total no. of variants, all variants detected by using whole-exome sequencing.