In contrast to CD19 or CD81 deficiency, biallelic CD21 (CR2) mutations causes a milder immunodeficiency: hypogammaglobulinemia, normal/mildly reduced serum IgM or IgA, fewer memory B cells, variable respiratory infections, and low-normal responses to protein and polysaccharide Ags (n = 4; Rosain et al., 2017; Thiel et al., 2012; Wentink et al., 2015). Here, CR2 is linked to immunodeficiency disease.