Holt–Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: Functional characterization of a de novo TBX5 mutation

Abstract

Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD.

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

“…At E13.5, Mta1 +/− mice have no apparent cardiac defects (Figure 2C). Tbx5 +/− mice exhibit partially penetrant cardiac defects as previously described, including ASD, VSD, and complete common atrioventricular canal (CCAVC), which includes both ASD and VSD components (Figure 2D) (Baban et al, 2014; Basson et al, 1994; Basson et al, 1999; Benson et al, 1996; Bruneau et al, 1999; Bruneau et al, 2001; McDermott et al, 2005). Tbx5 +/− ; Mta1 +/− heterozygous null embryos all demonstrated septal defects (19/19), a higher frequency of septal defects than either single heterozygote alone (0/14 for Mta1 +/− and 12/16 for Tbx5 +/− ) (p = 7.1E-9 vs. WT and p = 0.035 vs Tbx5 +/− ) (Figure 2E–J).…”

“…This hypothesis is further supported by our observations that Tbx5 +/− ; Mta1 +/− compound heterozygous mice have a higher frequency of cardiac septal defects than either single heterozygote alone (Figure 2J). AVSDs have been reported in 18 HOS patients, and 10 have been characterized to date (Baban et al, 2014). Of these, 6 of the mutations lead to the introduction of a stop codon before the TBX5 NID , and one mis-sense mutation maps within the TBX5 NID and ablates the TBX5-NuRD interaction (Figure 5K).…”

Complete atrioventricular septal defect in the era of prenatal diagnosis

“…The spectrum of cardiac malformations in Noonan syndrome is represented classically by pulmonary stenosis, with or without dysplastic pulmonary valve and hypertrophic cardiomyopathy; CAVSD coming on the second place as frequency, being reported in 13.8% of cases [50]. Holt Oram syndrome is characterized by the concomitant presence of heart and limb anomalies, the cardiac malformation could be either ASD, VSD or CAV [51,52]. VACTERL association has also been reported in the presence of a CAVSD [31].…”

Inherited progressive cardiac conduction disorders

“…Holt-Oram syndrome is characterized by radial ray upper limb abnormalities and cardiac septation defects with an autosomal dominant transmission pattern. The septal defects consist of secundum ASD, muscular ventricular septal defects or atrioventricular septal defects and may also be associated with aortic coarctation [57]. Affected patients also present various degrees of conduction disorders, such as sinus bradycardia and atrio-ventricular block, even in the absence of overt structural heart disease [58].…”