Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects

Abstract

Editor—Microdeletions of chromosomal region 22q11.2 (del22q11) have been associated with several genetic disorders, including DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAFS).1 The major clinical features associated with del22q11 are conotruncal heart defects, hypoplastic or aplastic thymus and parathyroid glands, facial dysmorphism, and learning difficulties. Many of the structures affected in the del22q11 syndrome are derivatives of the branchial apparatus, which is populated by the rostral neural crest cells. This has led to the hypothesis that haploinsufficiency of a gene(s) within the deleted region disrupts the development of these structures. The majority of patients carry a common ∼3 Mb deletion2 3 and over 20 genes have been mapped to the deleted region. The phenotypic features seen in association with the 22q11.2 deletion are highly variable, even among family members with the same sized deletion.4 5Monozygotic twins with discordant phenotypes have also been reported.6 Thus, additional factors, such as genetic background and environment, can modify the effect of haploinsufficiency of genes within 22q11.2. Recent studies have shown that mice heterozygously deleted (Df1/+) for part of the region of mouse chromosome 16 homologous to the DGS/VCFS region of 22q11.2 have heart defects similar to those found in DGS/VCFS patients.7 On a different genetic background these mice have been found also to have thymic defects.8 Several genes are located within the Df1 deleted region, including Tbx1. TBX1 is a member of the T box gene family of DNA binding transcription factors. T box genes have been shown to play an important role in the regulation of developmental processes.9 10 Haploinsufficiency of two T box genes, TBX3 and TBX5 , are associated with the human genetic diseases ulnar-mammary syndrome and Holt-Oram syndrome, respectively.11-13 A targeted deletion of Tbx1 has …