Somatic mosaicism in adult‐onset TNF receptor‐associated periodic syndrome (TRAPS)

Abstract

Background Somatic mosaicism is to date an uncommon finding in genetic autoinflammatory syndromes such as Cryopyrin‐associated periodic syndrome, Blau syndrome, and TNF receptor‐associated periodic syndrome (TRAPS). However, somatic mosaicism may be particularly important in adult‐onset or atypical phenotypes of these conditions. Herein, we report a unique adult‐onset TRAPS patient presenting with intermittent daily fever for 3 weeks, rash, peritonitis, and lymphadenopathy, who was found with hematopoietic mosaicism involving different white blood cell populations. Methods Patient's lymphocyte genomic DNA was initially analyzed by periodic fever seven‐gene next‐generation sequencing panel. Genomic DNAs extracted from patient's hair roots, buccal swab, and subpopulations of white blood cells were subsequently examined on the identified TNFRSF1A variant using Sanger sequencing. Results A de novo mosaic missense variant, c.265 T>C(p.Phe89Leu), in the TNFRSF1A gene was found in the patient's buccal swab, B cells, neutrophils, and NK cells but not detected in monocytes, T cells, and hair roots. Conclusion These data provide additional information about somatic mosaicism in autoinflammatory conditions and provide new insights regarding cellular players that are indispensable for the phenotypic expression of TRAPS.

Monogenic Adult-Onset Inborn Errors of Immunity

“…Mutations can have different and multiple impacts on protein function, either by affecting the cleavage of the extracellular domain preventing the release of soluble receptors (‘shedding effect’) attenuating inflammatory response or by expressing a mutant TNF-R1 alongside the WT resulting in a dysregulated inflammatory response ( 179 ). Adult-onset phenotypes are associated with low penetrance variants such as p.R92Q or p.P46L ( 150 ) but also somatic mosaicism has been described in two cases of adult-onset TRAPS ( 151 , 152 ). Clinical features may range from atypical images such as isolated recurrent pericarditis to more typical but adult-onset periodic fever syndromes with serositis, myalgia/arthralgia, erythematosus skin lesions, periorbital edema, and, in case of long-standing uncontrolled inflammation, amyloidosis ( 173 ).…”

Improving Diagnosis and Clinical Management of Acquired Systemic Autoinflammatory Diseases

“…One was a 41-year-old gentleman with a deletion mutation in TNFRSF1A (p.Ser86_Glu93del) and 7.6% whole blood mutant allele frequency. 20 The other was a 60-year old gentleman in whom the de novo missense mutation (p.Phe89Leu) was detected in the patients NK cells, neutrophils, and B cells, though not in monocytes and T cells. 21 …”

“…One was a 41-yearold gentleman with a deletion mutation in TNFRSF1A (p.Ser86_Glu93del) and 7.6% whole blood mutant allele frequency. 20 The other was a 60-year old gentleman in whom the de novo missense mutation (p.Phe89Leu) was detected in the patients NK cells, neutrophils, and B cells, though not in monocytes and T cells. 21 BS is a granulomatous autoinflammatory syndrome occurring due to mutations in the NOD2 gene, typically presenting in early childhood with cutaneous sarcoidosis, granulomatous arthritis, and uveitis.…”

Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

“…Another low-penetrance variant p.Thr90Ile (T61I) was described in 49% of Japanese patients with SAIDs, however the clinical significance of this variant remains unclear [22]. Recently, there were two reports of somatic variants in patients with adult-onset TRAPS [24][25][26]. Deep sequencing revealed a 24 bp in-frame deletion present in hematopoietic cells, nail, hair, and in sperm, suggesting gonadal mosaicism in one patient [25].…”