Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a Dutch family: evidence for a TNFRSF1A mutation with reduced penetrance

Abstract

Mutations of the tumor necrosis factor receptor 1 (TNFRSF1A) gene underly susceptibility to a subset of autosomal dominant recurrent fevers (ADRFs). We report on a two-generation six-member Dutch family in which a novel R92P mutation and reduced plasma TNFRSF1A levels were found in all the children, including two who are unaffected. However, only the daughter proband and father exhibited a typical TNF-receptor associated periodic syndrome (TRAPS) phenotype. PCR-RFLP analysis revealed that the mutation was not present in 120 control chromosomes from unaffected Dutch individuals. As this R92P mutation is present in two unaffected carriers it appears to be less penetrant than previously reported TNFRSF1A mutations involving cysteine residues in the extracellular domains.

Identification of a novel mevalonate kinase gene mutation in combination with the common MVK V377I substitution and the low-penetrance TNFRSF1A R92Q mutation

“…12 Heterozygosity for this low-penetrance mutation is expected to augment the intensity of the autoinflammatory response, 13,14 thereby resulting in a more severe phenotype, especially as HIDS has been shown to be associated with increased TNF and soluble TNF receptor levels. 15 From a clinical standpoint, however, this appears not to be the case in our proband.…”

An Israeli Arab patient with a de novoTNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome

“…To further investigate the possibility of a de novo TNFRSF1A mutation in the proband, 3-loci microsatellite haplotyping was performed on the 5 family members (6). The proband and both of the siblings who were studied inherited a common paternal haplotype, whereas that inherited from the mother was unique to the proband, suggesting that the mutation had arisen on the chromosome inherited from the mother (Figure 1).…”

“…The P46L variant may be relatively frequent in the Arab population, but its potential to cause clinical disease in this ethnic group is not yet clear. Another TNFRSF1A mutation with reduced penetrance, R92P, has recently been shown to cause TRAPS in a Dutch family (6).…”

Tumour necrosis factor receptor-associated periodic syndrome with a novel mutation in the TNFRSF1A gene in a Japanese family

“…In the C70Y mutation, two of the ten mutationpositive family members were asymptomatic, showing a penetrance of 80% [6]. Reduced penetrance described in some TRAPS mutations has been hypothetically explained by gene environment interactions, polymorphisms of background genes involved in TNF-a signalling pathways and varying thresholds for modifier protein function [1]. These factors may contribute to the discrepancy between genotype and phenotype in the presented family.…”