Submission Details

CD19 was first reported in relation to autosomal recessive immunodeficiency, common variable, 3 in 2006 (van Zelm MC, et al., 2006, PMID: 16672701). On mature B cells, CD19, CD81, CD21 and CD225 form the CD19 complex that signals in conjunction with the B cell antigen receptor (BcR), thereby decreasing the threshold for BcR-dependent signaling. Biallelic variation in this gene thus results in profound hypogammaglobulinemia due to a poor response to antigen. These patients are characterized by moderately severe hypogammaglobulinemia, impaired antibody responses on vaccination, and impaired memory B-cell formation. This gene-disease relationship is supported by both genetic and experimental evidence. At least eight variants (missense, splice site, and frameshift) have been reported in seven probands (PMIDs: 16672701, 21159371, 24684239, 34490048 and 21330302) and three additional affected family members. A role in disease is supported by the function of CD19 in lowering the threshold for antigen receptor stimulation (PMID: 1373518), which is disrupted in patient cells (PMID: 16672701). Expression of CD19 during B-cell differentiation provides further evidence; the surface molecule CD19 appears early and remains on the B cell until it differentiates into a plasma cell (PMID: 6408173). A CD19-/- mouse model recapitulates the profound deficiency in responding to protein antigens as well as impaired response to vaccination (PMID: 7543183) and live virus (PMID: 9653091). Recapitulation of hypogammaglobulinemia in the CD19-/- mouse can be rescued by human CD19 (PMID: 9144478). In summary CD19 is definitively associated with autosomal recessive immunodeficiency, common variable, 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.