Combined Immunodeficiency

Gene: RELB

Green List (high evidence)

2 unrelated adults with childhood onset severe and recurrent viral, bacterial, and fungal diseases, and combined T- and B-cell immunodeficiency and autoantibodies neutralizing type I interferons (IFNs). WES identified biallelic loss-of-function variants in RELB gene. P1 had a homozygous variant (p.Q72Tfs*152) which segregated with the parents and healthy siblings. P2 had a maternally inherited variant (p.E145K) and a de novo variant (p.P364L), with parental linkage confirmed by a microsatellite panel analysis.

There was a resulting deficiency of functional RelB which impaired the induction of NFKB2 mRNA and NF-κB2 protein by lymphotoxin in the fibroblasts of the patients. These defects were rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remained intact. Both patients had low proportions of naïve CD4+ and CD8+ T cells and of memory B cells. Their naïve B cells could not differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells was strongly impaired in vitro. Both patients produced neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens.

Created: 3 Oct 2024, 9:01 p.m. | Last Modified: 3 Oct 2024, 9:01 p.m.

Panel Version: 1.73

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
T-cell and B cell immunodeficiency; Immunodeficiency 53, OMIM #617585,

Publications

• PMID: 39231201

I don't know

3 related patients (unrelated to kindred reported in PMID: 26385063) with predominately severe autoimmune manifestations involving the liver, gut, lung, and skin, as well as repeated infection, and the range of patient ages (4–18 years). Homozygous mutation in RelB (P364L), RelB protein by Western blotting revealed markedly reduced levels compared to control, but not a complete absence of RelB as observed in RelB null cases. Functional studies demonstrating dysregulation of the NFκB main pathway with marked skewing towards pro-inflammation.
? Green given now multiple kindreds

Created: 24 Nov 2023, 1:58 a.m. | Last Modified: 24 Nov 2023, 1:58 a.m.

Panel Version: 1.51

Phenotypes
Complex autoimmunity

Publications

• PMID: 36402602

I don't know

Single family reported, functional data.
Sources: Expert list

Created: 3 Apr 2020, 3:42 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Immunodeficiency 53, MIM# 617585; T cells: normal number, poor diversity, poor function; recurrent infections

Publications

• 7834753
• 26385063