What is the role of genetics in the pathophysiology of immunoglobulin A deficiency (IgAD)?

Updated: May 15, 2018
  • Author: Marina Y Dolina, MD; Chief Editor: Michael A Kaliner, MD  more...
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Answer

Missense mutations in one allele of TACI were found in 4 of 19 unrelated individuals with CVID and in 1 of 16 individuals with SIgAD. The B cells from individuals with the TACI mutations expressed TACI but did not produce IgG and IgA in response to a TACI ligand, a finding thought to reflect impaired isotype switching. [20, 21, 6, 22, 23]

IgAD has been noted to evolve into CVID and is often observed in pedigrees that contain individuals with CVID. [24] Evidence for a common pathogenesis of CVID and IgAD include shared susceptibility alleles of major histocompatibility complex class III genes (D locus), [25] a similar spectrum of IgG subclass deficiencies, a gradual decline of immunoglobulin levels in concordant siblings, and the development of CVID in some patients with IgAD.

Previous studies of multiple-case families of patients with IgAD showed a higher prevalence of CVID among close relatives than in the general population. In multiple-case families with dominant transmission of CVID and IgAD, CVID was usually present in parents, followed by IgAD in the descendants. That study indicated the presence of a predisposing locus in the proximal part of the major histocompatibility complex. The recurrence risk was found to depend on the sex of the parents transmitting the defect. Affected mothers were more likely to produce offspring with IgAD than affected fathers. [8, 26, 27, 7]

IgAD has been reported in patients with constitutional chromosome 18 abnormalities, and a case series of 83 cases of 18p- syndrome showed an increased frequency of IgAD; however, attempts to identify a specific locus on chromosome 18 have not been successful. [7]


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