Absence of <i>NLRP3</i> somatic mutations and <scp>VEXAS</scp>‐related <i>UBA1</i> mutations in a large cohort of patients with Schnitzler syndrome

Abstract

Schnitzler's syndrome (SchS) is an extremely rare systemic autoinflammatory disease (SAID) characterized by a late onset of urticarial rash, recurrent fever, bone pain, arthralgia, elevated acute-phase reactants, and a monoclonal gammopathy involving IgMκ chains (classical type) and rarely IgG (variant type). To date, about 300 cases have been reported worldwide.1 The diagnosis of SchS is currently based on a set of clinical criteria, that is, the Strasbourg diagnostic criteria.2 It is of prime importance to establish this diagnosis given the therapeutic efficacy of interleukin-1 antagonists.3 No genetic predisposition has been formally identified so far. Two myeloid lineage-restricted somatic NLRP3 mutations were reported in 2015 in two SchS patients with the IgGκ variant type.4 Nevertheless, no NLRP3 mutation was identified in subsequent studies involving 32 SchS patients.5, 6 More recently, somatic mutations in exon 3 of UBA1 were reported in a syndrome affecting men with adult-onset SAID and named VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic).7 Notably, in this first VEXAS study, 20% of the patients presented multiple myeloma or monoclonal gammopathies of unknown significance (MGUS), thereby making UBA1 a potential candidate gene for SchS. These data prompted us to assess the contribution of NLRP3 and UBA1 somatic mutations, as well as of the main genes so far involved in SAID patients with cutaneous lesions in SchS pathophysiology. To this end, we screened for mutations of all these genes in the largest cohort of SchS patients constituted so far (40 unrelated cases) and at the origin of the validation of Strasbourg diagnostic criteria of SchS.2 We performed deep-targeted next-generation sequencing (NGS—mean sequencing depth of 943X) of 19 genes so far involved in SAIDs with cutaneous manifestations (NLRP3, NLRC4, MEFV, MVK, TNFRSF1A, IL1RN, IL36RN, LPIN2, PSTPIP1, TNFAIP3, IL36RN, CARD14, IL10, IL10RA, IL10RB, NOD2, PLCG2, LYN, and NLRP1), and Sanger sequencing of exon 3 of UBA1 (NM_003334) in all patients. None of the 40 SchS patients carried a somatic NLRP3 mutation. Notably, the two previously reported patients with a diagnosis of SchS and an NLRP3 mosaic mutation4 had a transient monoclonal IgG, an observation raising the possibility of a late-onset NLRP3-AID diagnosis. Indeed, late-onset urticarial lesions can represent the main clinical manifestation in patients with NLRP3 mosaic mutations.8 As for UBA1, the gene involved in VEXAS patients among whom 20% have multiple myeloma or MGUS,7 no somatic mosaic mutation was identified in the third exon of UBA1 in our cohort of 40 patients with SchS. These results, therefore, do not support the hypothesis of UBA1 somatic mutations in SchS pathophysiology. The study of 18 other genes involved in a SAID phenotype associated with cutaneous manifestations identified no somatic mosaic mutations in the 40 SchS patients. We, however, identified 33 rare heterozygous germline variations (Table S1). According to the American College of Medical Genetics recommendations used to assess their pathogenicity, 24 variations were classified as likely benign and 9 as variations of unknown significance (VUS) (i.e., 4 in NLRP1, 2 in IL10RA, 1 in IL10RB, 1 in NOD2, and 1 in TNFRSF1A) (Table S1). Although 4 variations were found in NLRP1, it is important to underline that all of them have a CADD (Combined Annotation-Dependent Depletion score, https://cadd.gs.washington.edu/) score <15, a finding that argues against their pathogenicity. In conclusion, no somatic or germline pathogenic variations have been identified in NLRP3, UBA1, and 18 other SAID genes involved in a disease phenotype associated with cutaneous signs, in the large cohort of 40 SchS patients at the origin of the validation of Strasbourg diagnostic criteria of SchS. Open access funding enabled and organized by ProjektDEAL. Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne University and the Société Française de Dermatologie. The authors have no conflict of interest to declare. Clinical features were collected through a standardized form. Written informed consents were obtained from all patients according to the French legislation and the principles of the Declaration of Helsinki. The study was approved by the research ethics committee from the Hôpitaux Universitaires de Strasbourg, France (N°ID RCB 2008-A01295-50). Appendix S1 Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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