A RELB germline loss of function (LOF) variant was first reported in a consanguineous family with combined immunodeficiency (CID) in 2015 (Merico et al, LymphoSign J., 2015). In this work, three children were identified to have a homozygous RELB nonsense variant through linkage analysis and whole genome sequencing followed by Sanger sequencing. The LOF was verified by demonstrating the reductions of RELB RNA and protein levels in the patients with this homozygous variant. This paper is not catalogued in PubMed but can be found at https://doi.org/10.14785/lpsn-2015-0005. Further analysis was performed in a follow up study, but genetic analysis was not performed (PMID: 26385063). The family is scored under this manuscript as the patients’ features and findings are described. Immunological defects of these three patients include dysplastic thymus, abnormal T cell repertoire and dysfunctional T and B cells (PMID: 26385063). A second nonsense variant has been reported (p.R307*), but there is no description of patient’s clinical features (PMID: 33083013). A third variant leading to a frameshift mutation was found in a patient with an oppurtunistic fungal infection and reduced T cell counts (PMID: 33791233). Heterozygous carriers have not been reported in the literature.
RelB is a component of alternative nuclear factor kappa-B (NF-kB) signaling pathway. RelB functions as a heterodimer with p52 NF-kB, which is a production of NIK activated p100 (NF-kB2) processing. RelB:p52 heterodimers are important for lymphoid organogenesis, humoral immunity, DC maturation and thymus development. The RelB protein is expressed in B lymphocytes and is absent in patients with RelB variant associated with CID. In vitro functional data demonstrate alterations in T and B cell activation, proliferation, and cytokine production (PMID:26385063). Mouse models of RelB deficiency and conditional RelB knockout systems showed defects in medullary thymic epithelial cells, Foxp3+ regulatory T cell development and were prone to develop autoimmunity, replicating some defects seen in patients with Omenn syndrome or colitis (PMID:28385374, 7845467). Hematopoietic stem cell transplant (HSCT) rescued T and B lymphocyte functions and improved quality life (PMID: 28552761). In summary, RELB has limited association with combined immunodeficiency.
This classification was approved by the ClinGen SCID-CID Working Group on 3/16/2023 (SOP Version 9 ).
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