Submission Details

Autosomal dominant

10/01/2020

The TNFRSF1A gene is located on chromosome 12 at 12p13.31 and encodes the TNF receptor superfamily member 1A protein, which is one of two membrane receptors bound by the proinflammatory cytokine TNF. TNFRSF1A was first reported in relation to familial periodic fever in 1999 (10199409: McDermott et al. 1999). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 19 unique missense variants have been reported in 20 cases from eight publications (10199409: McDermott et al. 1999; 10902757: Dode et al. 2000; 13130484: Aganna et al. 2003; 16508982: D'Osualdo et al. 2006; 22566169: Jesus et al. 2012; 23322460: Havla et al. 2013; 22343913: Lee et al. 2013; 25888769: Greco et al. 2015). More evidence is available in the literature, but the maximum score for probands with other variant type with some evidence of gene impact (7 pts) has been reached. This gene-disease relationship is supported by the biochemical function of TNFR1 signaling via two opposing pathways that lead to either apoptosis via caspase activation or to cellular survival and inflammation via the activation of NF-κB, functional alteration in patient and non-patient cells demonstrating reduced soluble TNFR1 impaired binding and intracellular signaling downstream of TNFR1, resulting in enhanced production of cytokines and chemokines (17666110: Kimberley et al. 2007; 16684962: Lobito et al. 2006; 20457915: Simon et al. 2010). In two different knock-in mouse lines with TRAPS-associated variants in TNFRSF1A, TNFR1 accumulated intracellularly and there was enhanced activation of proinflammatory signaling. Heterozygous mice were hypersensitive to lipopolysaccharide (LPS), an endotoxin, which was also observed in TRAPS patient cells (20457915: Simon et al. 2010). In summary, TNFRSF1A is definitively associated with familial periodic fever. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

10199409 10902757 13130484 16508982 22566169 23322460 22343913 25888769 17666110 20457915 16684962