Disease relevance of DiGeorge Syndrome

• A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11 [1].
• It can, however, result from a single gene defect either as part of a syndrome (e.g. van der Woude syndrome, Treacher-Collins syndrome, velo-cardio-facial syndrome) or as an isolated phenotypic effect (e.g. X-linked cleft palate; non-syndromic, autosomal dominant orofacial clefting) [2].
• When these data are pooled with recent results from the literature, 24 de novo DGS, velo-cardio-facial syndrome (VCFS) and isolated conotruncal cardiac disease deletions are found to be of maternal origin and 8 of paternal origin, yielding a chi 2 of 8 with a probability level lower than 0.01 [3].
• The predicted protein is similar to those of the newly characterized Clostridium perfringens enterotoxin receptors and is the mouse homolog of a recently described human cDNA clone, which is hemizygously deleted in individuals with velo-cardio-facial syndrome and DiGeorge syndrome [4].
• A small number of patients with Wiskott-Aldrich syndrome, natural killer cell deficiency, DiGeorge syndrome and chronic mucocutaneous candidiasis were also registered [5].

Psychiatry related information on DiGeorge Syndrome

• The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development [6].
• Abstract Background Velo-cardio-facial syndrome (VCFS, 22q11.2 deletion) is characterized by severely delayed language development [7].

High impact information on DiGeorge Syndrome

• TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome [8].
• Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome [9].
• Hypoparathyroidism and the DiGeorge syndrome [10].
• VEGF: a modifier of the del22q11 (DiGeorge) syndrome [11]?
• Inactivation of TGFbeta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome [12].

Chemical compound and disease context of DiGeorge Syndrome

• Unmasking of hypoparathyroidism in familial partial DiGeorge syndrome by challenge with disodium edetate [13].
• Response to thymopoietin pentapeptide in patient with DiGeorge syndrome [14].
• The teratogenic effects of a bis(dichloroacetyl)diamine on hamster embryos. Aortic arch anomalies and the pathogenesis of the DiGeorge syndrome [15].
• Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition [16].
• Localization of the human mitochondrial citrate transporter protein gene to chromosome 22Q11 in the DiGeorge syndrome critical region [17].

Biological context of DiGeorge Syndrome

• Deletions of chromosome 22q11.2 have been associated with distinct phenotypes that result from a failure to form derivatives of third and fourth branchial arches, including DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS) [18].
• Using an animal model system and depletion-rescue strategies, we have addressed the requirement and functions of armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) and p120 catenins in early vertebrate embryogenesis [19].
• We describe the relative ordering, by fluorescence in situ hybridization, of cosmid loci and translocation breakpoints in the DiGeorge syndrome (DGS) critical region of chromosome 22 [20].
• Since many of the structures affected in DiGeorge syndrome derive from these Hira expressing cell populations we propose that haploinsufficiency of HIRA contributes to at least some of the features of the DiGeorge phenotype [21].
• The proximal portion of human chromosome 22q appears to carry genes implicated in the pathogenesis of various developmental disorders, including the cat eye syndrome (CES) and the DiGeorge syndrome (DGS) [22].

Anatomical context of DiGeorge Syndrome

• Thus, TGFbeta signal modulation in neural crest differentiation might play a crucial role in the etiology of DiGeorge syndrome [12].
• Bruton's XLA and DiGeorge syndrome patients show that two basic immune systems are distinct from each other in humans - thymus-dependent cell-mediated immunodeficiencies vs. antibody-based immunodeficiencies [23].
• Velocardiofacial syndrome and DiGeorge syndrome have not previously been associated with central nervous system degeneration [24].
• RanBP1, a velocardiofacial syndrome/DiGeorge syndrome candidate gene, is expressed in the frontonasal processes, branchial arches, aortic arches, and limb buds [25].
• T cell receptor repertoire and function in patients with DiGeorge syndrome and velocardiofacial syndrome [26].

Gene context of DiGeorge Syndrome

• The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11 [27].
• Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation [28].
• HIRA homologs are expressed in a regulated fashion during mouse and chicken embryogenesis, and the human gene is a major candidate for the DiGeorge syndrome and related developmental disorders caused by a reduction to single dose of a fragment of chromosome 22q [29].
• We now report that one of them, ZNF74 gene, is hemizygously deleted in 23 out of 24 DiGeorge syndrome patients tested [30].
• Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development [31].

Analytical, diagnostic and therapeutic context of DiGeorge Syndrome

• Complete DiGeorge syndrome (cDGS) is a congenital disorder characterized by typical facies, thymic aplasia, susceptibility to infections, hypoparathyroidism and conotruncal cardiac defect [32].
• Molecular cloning and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome chromosomal region [33].
• To demonstrate the efficiency, sensitivity, and specificity of PRINS in the diagnosis of microdeletions, we studied groups of patients with Prader Willi/Angelman (PWS/AS) syndrome and DiGeorge/velocardiofacial syndrome (DGS/VCFS) [34].
• Patients wiith DiGeorge syndrome have no delayed hypersensitivity, cannot be actively sensitized with dinitrochlorobenzene, reject allografts poorly, and have no lymphocytic response to phytohemagglutinin antigens [35].
• These data correlate well with the heterogeneity of the DiGeorge syndrome and variable results seen with human CTF transplantation [36].

References