Genetic modifiers of the physical malformations in velo-cardio-facial syndrome/DiGeorge syndrome

Abstract

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), the most common micro-deletion disorder in humans, is characterized by craniofacial, parathyroid, and thymic defects as well as cardiac outflow tract malformations. Most patients have a similar hemizygous 3 million base pair deletion on 22q11.2. Studies in mouse have shown that Tbx1, a T-box containing transcription factor present on the deleted region, is likely responsible for the etiology of the syndrome. Furthermore, mutations in TBX1 have been found in rare non-deleted patients. Despite having the same sized deletion, most VCFS/DGS patients exhibit significant clinical variability. Stochastic, environmental and genetic factors likely modify the phenotype of patients with the disorder. Here, we review mouse genetics studies, which may help identify possible genetic modifiers for the physical malformations in VCFS/DGS.

Figure 1

Human 22q11.2 genomic region. The horizontal line represents chromosome 22, with the centromere on the left. The recurrent chromosomal deletions (represented by blue boxes) share common breakpoints on 22q11.2. The breakpoints are in segmental duplications termed LCR22s (red rectangles). The location of TBX1 and CRKL is indicated by the black rectangles.

Figure 2

Hypothetical genetic pathways of Tbx1 in the development of the pharyngeal apparatus. Tbx1 is expressed in the pharyngeal ectoderm (green), mesoderm (yellow), and endoderm (blue). In the mesoderm, the gene activates fibroblast growth factor (FGF) family members Fgf8 and Fgf10, as well as Pitx2 (arrows). Tbx1 is also implicated in an auto-regulatory loop with Foxa2 in the pharyngeal mesoderm (double-headed dashed arrows). In the endoderm, the gene activates Fgf8. Sonic hedgehog (Shh), from the endoderm, regulates expression of Tbx1 in the mesoderm and in the endoderm, possibly through regulation of Foxc2 and Foxa2, respectively (dashed arrows). Tbx1 together with Crkl negatively regulates activation of the retinoic acid (RA) signaling pathways in all three germ layers (arrows).