Submission Details

CR2, also referred to as CD21, was first reported in relation to autosomal recessive common variable immunodeficiency (CVID; OMIM # 614699) in 2012 (Thiel J et al., PMID: 22035880). CR2-associated CVID is a heterogeneous disorder characterized by hypogammaglobulinemia with some patients also presenting with recurrent infections, particularly respiratory infections. Importantly, individuals carrying biallelic pathogenic CR2 variants may present with the immunological phenotype of hypogammaglobulinemia and low levels of class-switched B cells in the absence of a clinical phenotype, such as recurrent infections (PMID: 30075290). It is currently unknown what proportion of affected individuals are currently asymptomatic or how likely they are to present with a clinical phenotype at a later age. Five variants (nonsense, frameshift, and canonical splice site) found that have been reported in three unrelated probands (and four probands total) as either compound heterozygous or homozygous in three publications are included in this curation (PMIDs: 22035880, 26325596, 28499783). The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 6234356, 8622941, 8624815, 1702139, 12479818, 22035880, 26325596). CR2 has been shown to be expressed on the majority of circulating mature human B cells and human follicular dendritic cells (PMID: 6234356, 2471772) and is part of the B-cell receptor complex (PMID: 1702139). CD19 (as well as CD81) is also a member of the B-cell receptor complex and has also been associated with common variable immunodeficiency (OMIM # 613493). Mouse models lacking expression of CR2/CR1 have decreased levels of antibody, particularly IgG, and have increased susceptibility to infection (PMIDs: 8622941, 8624815, 12479818). Expression of human CR2 in CR2/CR1-/- mice rescues secondary responses to T-dependent antigen in CR2/CR1-/- mice (PMID: 21269698). B cells from patients with CR2-associated CVID decreased responses to antigen and AID expression (PMIDs: 22035880, 26325596). In summary, CR2 is definitively associated with autosomal recessive CVID. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Notably, this curation does not assess the reported relationship between CR2 and susceptibility to systemic lupus erythematosus (OMIM # 610927).