Molecular genetics of congenital atrial septal defects

Abstract

Congenital heart defects (CHD) are the most common developmental errors in humans, affecting 8 out of 1,000 newborns. Clinical diagnosis and treatment of CHD has dramatically improved in the last decades. Hence, the majority of CHD patients are now reaching reproductive age. While the risk of familial recurrence has been evaluated in various population studies, little is known about the genetic pathogenesis of CHD. In recent years significant progress has been made in uncovering genetic processes during cardiac development. Data from human genetic studies in CHD patients indicate that the genetic aetiology was presumably underestimated in the past. Inherited mutations in genes encoding cardiac transcription factors and sarcomeric proteins were found as an underlying cause for familial recurrence of non-syndromic CHD in humans, in particular cardiac septal defects. Notably, the cardiac phenotypes most frequently seen in mutation carriers are ostium secundum atrial septal defects (ASDII). This review outlines experimental approaches employed for the detection of CHD-related genes in humans and summarizes recent findings in molecular genetics of congenital cardiac septal defects with an emphasis on ASDII.

Fig. 1

Strategies for the identification of gene mutations associated with CHD. The selection of potential gene candidates can be achieved after identification of a chromosomal locus (kindred-based haplotype mapping or cytogenetic abberations) or via a rationale based on other experimental findings (candidate gene approach). Pathogenicity of novel sequence variants should be evaluated by family study, genotyping of adequate controls and functional assays

Fig. 2

Schematic presentation of mutations found in TBX5 as a cause for Holt–Oram syndrome. Mutations are described at the protein level according to reference AAC04619.1. The majority of mutations are located in the DNA-binding T-box domain of TBX5. Intronic and somatic mutations are not included

Fig. 3

Schematic representation of NKX2.5, GATA4 and TBX20 protein structure with exonic germline mutations related to non-syndromic CHD indicated. All mutations related to ASDII are represented on the top. Mutations found in patients with CHD other than ASDII are shown below the structural domains. All mutations which were evaluated by family and/or functional studies are represented in bold letters. Mutations which were found in patients with dilated cardiomyopathy are marked with an asterisk. Somatic and intronic mutations are not included