Variable immune deficiency related to deletion size in chromosome 22q11.2 deletion syndrome

Abstract

The clinical features of 22q11.2 deletion syndrome include virtually every organ of the body. This review will focus on the immune system and the differences related to deletion breakpoints. A hypoplastic thymus was one of the first features described in this syndrome and low T cell counts, as a consequence of thymic hypoplasia, are the most commonly described immunologic feature. These are most prominently seen in early childhood and can be associated with increased persistence of viruses. Later in life, evidence of T cell exhaustion may be seen and secondary deficiencies of antibody function have been described. The relationship of the immunodeficiency to the deletion breakpoints has been understudied due to the infrequent analysis of people carrying smaller deletions. This manuscript will review the immune deficiency in 22q11.2 deletion syndrome and describe differences in the T cell counts related to the deletion breakpoints. Distal, non-TBX1 inclusive deletions, were found to be associated with better T cell counts. Another new finding is the relative preservation of T cell counts in those patients with a 22q11.2 duplication.

Keywords: DiGeorge; IgG; T cells; breakpoints; deletion size; low copy number repeats.

FIGURE 1

Chromosome 22q11.2del breakpoints commonly observed. This schematic diagram demonstrates the most common breakpoints observed in 22q11.2del. The most common deletion is A–D and includes TBX1. The location of TBX1 is shown with a star. The percentages next to each deletion schematic indicate the frequency. In addition, there are rarer deletions not mediated by the low copy number repeats (LCRs) indicated in the figure and larger deletions that extend distal to the region shown in the figure. Duplications are similarly variable but most often lead to duplication of the A–D region

FIGURE 2

22q11.2 deletions including TBX1 gene region are associated with CD3+ lymphopenia due to decreased CD4+ count. Charts of patients were retrospectively reviewed following approval from the Children’s Hospital of Philadelphia Institutional Review Board. Peripheral blood absolute (a) CD3+ counts, (b) CD4+ counts, (c) CD19 counts, and (d) natural killer CD3−/CD16+ CD56+ counts were determined by flow cytometry. Data were extracted from the patients’ medical records from Immunology visit near 12 months’ of age. 22q11.2 deletion patients with a TBX1 containing deletion (A–B, A–C, A–D deletions, n = 52), were compared to patients with 22q11.2 deletion with deletions not containing TBX1 (B–D, C–D, D–E, D–F deletions, n = 8), and patients with 22q11.2 duplications (n = 11). Bars demonstrate mean and error bars indicate standard deviation. p values refer to an unpaired t-test