significantGenetic discoveryMarch 1, 2015

Eurofever/PRINTO genotype-phenotype study in 158 TRAPS patients

TNF Receptor-Associated Periodic Syndrome →

Summary

Ter Haar et al. (2015) analyzed 158 TRAPS patients in the Eurofever registry, confirming that cysteine-disrupting TNFRSF1A mutations cause the most severe phenotype with highest amyloidosis risk (24%), while T50M and R92Q variants present with milder, often self-limited disease. These findings established genotype-based risk stratification for clinical management.

High-penetrance pathogenic variants. Disrupt disulfide bonds in CRD1/CRD2 of the TNFR1 extracellular domain. Associated with severe phenotype and high amyloidosis risk (24% vs 2% for non-cysteine).

TNFRSF1AT50M (p.Thr79Met)

Most common high-penetrance pathogenic variant. Affects a conserved hydrogen bond critical for protein folding in CRD1. Despite not disrupting a cysteine, carries high disease penetrance and amyloidosis risk similar to cysteine mutations.

TNFRSF1AR92Q (p.Arg121Gln)

Low-penetrance variant of uncertain pathogenic significance. Present in 1.2–4% of healthy Caucasians. Associated with milder disease, shorter episodes, less familial aggregation (19% vs 64%), and higher spontaneous resolution rates. Classified as INSAID Group B (uncertain significance).

TNFRSF1AP46L (p.Pro75Leu)

Another low-penetrance variant. Found at high frequency in sub-Saharan West African populations. Clinical significance debated — may be a benign polymorphism in some ethnic backgrounds.