Submission Details

The relationship between TRAF3 and TRAF3 Haploinsufficiency, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of May, 2023. Note, at the time of curation, OMIM did not indicate an associated disease entity for this gene. TRAF3 encodes tumor necrosis factor receptor (TNFR)-associated factor 3, which is involved in signaling and participates in the signal transduction of CD40 to activate immune response. TRAF3 haploinsufficiency presents as an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia (Rae et al, 2022; PMID: 32484799). TRAF3 was first reported in relation to autosomal dominant TRAF3 haploinsufficiency in 2022 (Rae et al, 2022; PMID: 32484799). This gene-disease relationship is supported by case-level and experimental data.

Summary of Case Level Data (8.5 points): Five unrelated probands have been reported with four heterozygous loss of function variants (nonsense and frameshift) resulting in reduced TRAF3 mRNA and protein expression (PMID: 32484799). The variant is de novo in two of the reported individuals, while segregation with disease was noted in two families. The mechanism of disease is expected to be haploinsufficiency. Two additional case reports suggest a disease phenotype related to TRAF3 missense variants with a likely dominant negative mechanism (PMID: 20832341, PMID: 36004314). Perez de Diego (PMID: 20832341) report the Arg118Trp variant as causative of susceptibility to acute, infection-induced (Herpes-specific) encephalopathy (MIM: 614849) based on functional evidence showing reduced protein expression; however, this variant is reported at a high frequency in gnomAD v2.1.1 (266 out of 129052 non-Finnish European alleles) and PMID: 32484799 shows that this variant confers an insignificant but increased odds ratio analyzed based on data from the UK Biobank, indicating that this variant may be risk factor. Therefore, this variant is not scored any points. Liew et al report the Arg338Trp variant in a patient with Mycobacterium infection, bronchiectasis, normal immunoglobulin levels and negative autoantibodies, supported by functional evidence, indicating a dominant negative effect. This variant is also not scored as the proband's phenotype and the disease mechanism are inconsistent with TRAF3 haploinsufficiency.

Summary of experimental data (3 points): This gene-disease relationship is supported by mouse model evidence. Homozygous TRAF3 knock-out mice progressively become runted and die by d10 post-birth, however histological studies reveal no gross defects (PMID: 8934568). Conditional knock-out of TRAF3 with B-cell and T-cell specific transgenic mice recapitulated many of the human phenotypes including lymphadenopathy, splenomegaly, hyperimmunoglobulinemia, susceptibility to infection and autoimmunity.

In summary, the level of evidence to support the gene-disease relationship of TRAF3 and autosomal dominant TRAF3 haploinsufficiency is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Antibody Deficiencies GCEP on May 30, 2023 (SOP Version 9).