Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TRAF3

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 12:01 p.m. | Last Modified: 24 Feb 2025, 12:01 p.m.

Panel Version: 7.26

Comment on list classification: There is sufficient evidence available now for the promotion of this gene to green rating in the next GMS update.

Created: 8 Nov 2024, 5:29 p.m. | Last Modified: 8 Nov 2024, 5:29 p.m.

Panel Version: 7.13

As reviewed by Dmitrijs Rots, PMID:35960817 reported nine patients from five unrelated families with an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. All affected individuals had heterozygous premature stop-codon variants in TRAF3 gene.

Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells.

Created: 8 Nov 2024, 5:25 p.m. | Last Modified: 8 Nov 2024, 5:25 p.m.

Panel Version: 7.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790

Publications

• 35960817

Green List (high evidence)

PMID: 35960817 described multiple patients with PID and variants in TRAF3

Created: 18 Oct 2024, 12:46 p.m. | Last Modified: 18 Oct 2024, 12:46 p.m.

Panel Version: 6.16

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

Publications

• PMID: 35960817

Red List (low evidence)

Single patient though strong circumstantial evidence of pathogenicity

Created: 29 Jun 2018, 3:51 p.m.

Publications

• 20832341

Red List (low evidence)

In OMIM TRAF3 is provisionally associated with {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}. Evidence cited in OMIM comes from Perez de Diego et al. (2010) (PMID: 20832341) who report a 18-year-old French female who had suffered from herpes simplex encephalitis (HSE) with a de novo missense change in TRAF3 (R118W). The analysis of patient's cells showed normal levels of TRAF3 mRNA, but severely reduced levels of TRAF3 protein. Expression of wildtype and mutant alleles in cell lines showed that the mutant was dominant-negative. Mikula et al. (2001)(PMID: 11296228) reported that mice lacking Craf1(TRAF3) died at mid gestation with placenta and liver anomalies. Chang et al. (2014)(PMID: 24378539) created mice deficient in Traf3 specifically in regulatory T (Treg) cells and concluded that TRAF3 is a signaling factor that mediates the effector functions of Treg cells, and is involved in induction of ICOS as a result of impaired ERK activation. No further evidence for association with from Gene2Phenotype or a search in PubMed.

Created: 27 Jun 2018, 9:26 a.m.

I don't know

Comment on publications: added publication to support gene-disease association

Created: 5 Jul 2018, 2:44 p.m.

Comment on list classification: Changed from Amber to Red until more info to support gene-disease association. Currently only one case reported in literature. Gene not present on any other PID related panels or within ESID or IUIS classifications. Request evidences /
immunological association of this gene from Victorian Clinical Genetics Services and GRID

Created: 5 Jul 2018, 2:43 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TRAF3 .PanelApp HGNC gene symbol check: TRAF3 . IUIS Disease: TRAF3 deficiency . IUIS Inheritance: AD .T cells: Normal or Increased activated T cells; low/normal iNK T cells, .B cells: N/A, .IUIS Other affected cells: CNS resident cells and fibroblasts. IUIS Associated features: Herpes simplex virus 1 encephalitis. IUIS Major category: Defects in Intrinsic and Innate Immunity. IUIS Subcategory: Herpes Simplex Encephalitis (HSE)

Created: 2 Jul 2018, 10:35 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s)
GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 19 Apr 2018, 11:28 a.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: TRAF3, PanelApp HGNC gene symbol check: TRAF3, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Defects in innate immunity / Herpetic encephalitis / Herpetic encephalitis (HSE)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TRAF3, GRID_Gene_Symbol: TRAF3, GRID_Transcript_ENS_Community submitted: ENST00000560371, GRID_Transcript_RefSeq: NM_145725.2, GRID_Transcript_ENS_used_on_Production: ENST00000560371

Created: 17 Apr 2018, 12:12 p.m.