Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus

Abstract

Septation defects and patent ductus arteriosus are the most common human cardiovascular malformations (CVMs). Genetic factors play a major part in the origin of these malformations. Recent molecular analyses have shed light on several mendelian forms. In the autosomal dominant Holt-Oram syndrome, both atrial and ventricular septal defects are inherited in association with limb deformity as a result of mutations in the gene encoding the TBX5 transcription factor. Mutations in the NKX2.5 transcription factor gene cause autosomal dominant familial atrial septal defects in association with progressive atrioventricular block as well as complex congenital heart disease. Common atrial syndromes in autosomal dominant Ellis-van Creveld syndrome arise in the context of axial skeletal and limb malformation as a result of mutations in the EVC gene, whose function is unknown. Patent ductus arteriosus occurs in several syndromic forms of congenital heart disease, including Holt-Oram syndrome. Recent analyses of autosomal dominant Char syndrome, which includes, with variable penetrance, patent ductus arteriosus as well as craniofacial and hand malformations, have shown that the syndrome is caused by mutations in the TFAP2B transcription factor gene. Ongoing analyses are poised to determine the contribution of these genes as well as others yet to be identified to common, sporadic forms of congenital heart disease.

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

“…[37][38][39][40] Patients with whole or partial chromosome 12q duplications (including the 12q24.21 region and TBX5 gene) have been described to have some of the cardiac features of HOS (mainly septal defects), other congenital anomalies and dysmorphism, but hardly any of the skeletal features. [41][42][43][44][45][46][47][48][49] This partially conforms to the prominent cardiac defects and milder limb defects seen in this family with the TBX5 duplication, therefore it seems expression of TBX5 must be finely regulated for normal cardiac and limb development. Postma et al 50 described a HOS family with predominantly cardiac defects and mild limb defects, with a novel gain-of-function missense mutation (Gly125Arg) in TBX5.…”

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

“…Conversely, genetic analysis of particular large families such as those studied herein can more easily lead to substantial results. The large number of subjects with PDA (n ¼ 11) compared to the average incidence of 1/2000 in general population, 22 its presence in three subjects with TAA or AD, and its cosegregation with TAA/AD (Figures 1 and 2) and the results of the segregation analysis strongly suggest the presence of a unique autosomal dominant genetic defect. None of the cases observed in this family occurred in the presence of particular neonatal circumstances such as those usually observed in sporadic PDA.…”

“…1,2 Empirically, penetrance levels for carrier subjects were set at: 0%o20 years old; 40% between 20 and 50 years old and 80%450 years old for TAA/AD, to take into account the likely age-dependent penetrance of the disease. 21 When 22 and a penetrance rate of 90%. The linkage analyses were performed using the M-LINK program implemented in the Linkage Package.…”

Essential Role for ADAM19 in Cardiovascular Morphogenesis

“…Congenital heart disease is the most common form of birth defects in humans, yet little is known about the underlying molecular causes (2,8,15,29,43,47). In light of the critical role of mouse ADAM19 in heart development, it will be interesting to determine whether certain types of human congenital heart defects are caused by mutations in ADAM19, which is located on human chromosome 5q33.3.…”