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New Aspects of Isotretinoin Teratogenicity
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
DiGeorge syndrome, a 22q11.2 deletion syndrome, is another neurocristopathy resembling retinoid embryopathy (83). The most studied gene of interest in the 22q11.2 deletion region is TBX1, encoding a T-box transcription factor (83). Tbx1-/- mice had a high incidence of cardiac outflow tract anomalies, hypoplasia of the thymus and parathyroid glands, abnormal facial structures, abnormal vertebrae, and cleft palate, leading to the conclusion that Tbx1 in humans is a key gene in the etiology of DiGeorge syndrome (84–86). Tbx1 controls cardiac NCC migration during arch artery development by regulating GBX2 expression in the pharyngeal ectoderm (87). Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice (86). In accordance, half dosage of this gene in humans causes most of the features of the DiGeorge or velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities (88). Recently, a strong genetic interaction between Tbx1 and p53 has been found. Intriguingly, genetic ablation of TP53, or pharmacological inhibition of p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants (88). As a result, disturbed Tbx1-p53 signaling is involved in the pathogenesis of DiGeorge syndrome.
Genetics
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Jane A. Hurst, Richard H. Scott
DiGeorge syndrome is due to a monoallelic deletion of chromosome 22q11 (del22q11.2) (Fig. 15.13). These microdeletions are typically ~3 Mb of genomic DNA and are not detectable by G-banded karyo-type. The TBX1 gene within the area of deletion is of particular importance in the phenotype.
Velo-cario-Facial Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Wendy R. Kates, Kevin Antshel, Wanda Fremont, Nancy Roizen, Robert J. Shprintzen
A number of studies have proposed candidate genes within the deleted region in relation to specific anomalies or groups of anomalies (29–32). At this time, it seems likely that at least two genes can be linked to some of the VCFS phenotype. Because the 22q11.2 genome is well preserved across species, its homolog has been isolated to mouse chromosome 16. Using animal models, investigators have determined that haploin-sufficiency of the gene TBX1 results in the same conotruncal heart anomalies commonly found inVCFS (31). The gene COMT (catechol-O-methyltransferase) has been linked to psychiatric disorders in relation to the metabolism and degradation of synaptic dopamine levels (30,33). COMT is responsible for the degradation of dopamines and therefore has been hypothesized to have an effect on neural transmission. COMT has been found to have a polymorphism, two alleles that have different activity levels with regard to their ability to degrade dopamines: a low secreting heat labile version, and a high secreting stable version (30). Hemizygosity for the low secreting version has been linked to a higher frequency of psychiatric disorders in individuals with VCFS (30). Both of these genes reside within the commonly deleted region for VCFS and all individuals who are FISH positive for the deletion will be missing single copies of TBX1 and COMT.
Hypoparathyroidism concomitant with macrothrombocytopenia in an elderly woman with 22q11.2 deletion syndrome
Published in Platelets, 2018
Hsiu-Chien Yang, Shih-Hua Lin, Yi-Ying Wu, Chih-Chien Sung
Numerous candidate genes have been linked to the different phenotype of 22q11.2DS. In 1999, TBX-1, a member of the T-box transcription factor family, was identified as one of the most vital gene controlling pharyngeal arch development. Therefore, haploinsufficiency in TBX1 compromises facial structure, parathyroid, and thymus development (1,3,7). In two studies, parathyroid hypoplasia associated with hypocalcaemia was found in approximately 50% of 22q11.2DS cases, typically in pediatric patients (1,3). However, 22q11.2DS may remain undiagnosed in adults because they may lack severe phenotypic features (8,9). A late-onset symptomatic hypocalcemia can be caused by increased calcium requirements with inadequate parathyroid hormone secretion (during adolescence, pregnancy, infection, or surgery) (10–12). Alternatively, the aging process and chronic kidney disease could aggravate hypocalcemia symptoms because of vitamin D deficiency. In this case, hypocalcemia symptoms exacerbated by chronic kidney disease and aging might be presented in the elderly life without cardiovascular abnormalities.
Association between the promoter methylation of the TBX20 gene and tetralogy of fallot
Published in Scandinavian Cardiovascular Journal, 2018
Xiaofei Yang, Qingyu Kong, Zhenghao Li, Min Xu, Zhifeng Cai, Cuifen Zhao
TBX20, a member of the TBX1 subfamily, has recently become a focus of research [18]. Studies on mouse models revealed that TBX20 is expressed in cardiac progenitor cells, developmental myocardium, and endothelial cells associated with endocardial cushion, which is the precursor structure of the cardiac valves and atrioventricular septa [19–21]. The abnormal development of the endocardial cushion can cause serious cardiac malformations, such as the transposition of great arteries, double outlet of the right ventricle, TOF, and the other atrioventricular canal abnormalities [22]. Previous studies showed that mutations in the TBX20 gene occur only in a small number of patients with TOF [23–25]. Meanwhile, the pathogenesis of TBX20 methylation in TOF is poorly studied.
22q11.2 microduplication syndrome and juvenile glaucoma
Published in Ophthalmic Genetics, 2018
Federico Di Matteo, Paolo Bettin, Giulia Ferrari, Marina Fiori, Carlo Ciampi, Emanuela Manfredini, Alessandro Rabiolo, Francesco Bandello
arch arteries development (8). TBX1 is a dosage sensible gene and deviations from normal values may lead to syndromic diseases. Its underexpression is the main causative factor for the DiGeorge\velocardiofacial syndrome (9,10). On the other hand, TBX1 gain-of-function mutations may result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions (2). However, some carriers show no phenotypic anomalies. Most of the systemic findings of our patients (i.e., craniofacial malformations, seizures, malignancies, and endocrine dysfunctions) can be related to TBX1 gene duplication.