We report on a combination of congenital malformations in a mother and her fetus harboring a heterozygous deletion encompassing the TBX5 and TBX3 genes, which are disease-causing in Holt-Oram and ulnar-mammary syndromes, respectively.
In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations.
As part of a larger study, high density, single nucleotide polymorphism (SNP) scanning was used to explore the relationship between TBX5 gene polymorphism and susceptibility to ventricular septal defect not associated with forelimb malformation in the Chinese Han population.
Our study strongly suggests that Cx40 deficiency accounts for many skeletal malformations in HOS and that Tbx5 regulation of Cx40 plays a critical role in the exquisite developmental patterning of the forelimbs and sternum.
Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities.
Holt-Oram syndrome (HOS) is a multiple malformation syndrome associated with congenital heart malformation (CHM) and caused by mutations in the TBX5 transcription factor.
We show for the first time TBX5 mutations in non-HOS associated cardiac malformations and we identified a novel missense mutation that would impact nuclear localization of TBX5.
These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.
Intrafamilial variations of the malformations strongly suggest that genetic background or modifier genes play an important role in the phenotypic expression of HOS.
These patterns of Tbx5 expression provide an embryologic basis for the prevalence of atrial septal defects (ostium primum and secundum), ventricular muscular septal defects, and left-sided malformations (endocardial cushion defects, hypoplastic left heart, and aberrant trabeculation) observed in patients with Holt-Oram syndrome.