We investigated a family with CVID and identified the heterozygous C104RTNFRSF13B mutation in two of the three index-children with CVID, a mother with selective immunoglobulin A deficiency, a mother with recurrent infections and a healthy grandfather.
Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus.
To examine the potential contribution of TNFRSF13B variants to CVID, we have applied an evolutionary approach by sequencing its coding region in 451 individuals belonging to 26 worldwide populations, in addition to controls, patients with CVID and selective IgA deficiency (IgAD) from Italy.
Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10<sup>-8</sup>) loci and association with a rare IFIH1 variant (p.Ile923Val).
Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD.
Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele sharing in the chromosome region 6p21 consistent with allelic associations in family-based and case-control studies and provided the evidence for a predisposing locus, termed IGAD1, in the proximal part of the MHC.
Of 110 haplotypes shared by 258 affected family members, a single haplotype (H1) was found in 44 pairs of affected relatives, accounting for the majority of the IGAD1 contribution to the development of IgAD/CVID in our families.
Haplotype analysis, linkage disequilibrium, and homozygosity mapping indicated that HLA-DQ/DR is the major IGAD1 locus, strongly suggesting the autoimmune pathogenesis of IgAD/CVID.
<b>Results:</b> By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals.