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.

CCN1 Mutation is Associated with Atrial Septal Defect

“…The extreme rarity of the mutation in the patient cohort, as also reported for the other ASD associated variants [3], and the exclusion of this variant in a very high number of ethnically well matched controls (our own 1015 controls and 2203 African Americans from the ESP dataset) are important points, as well as the exclusion of known ASD disease genes. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the IGFBP module harboring the important 5 "IGFBP motif" found in all IGFBPs and CCN proteins [15] suggesting a disturbed protein folding (strengthened by special bioinformatic tools).…”

“…Indeed, it is most likely that the majority of patients with ASD have a complex, multifactorial aetiology [3]. But one should also note that the cardiac phenotype most frequently seen in published mutation carriers are ASDs [3].…”

“…Numerous advances in understanding the molecular pathways and genes involved in septal defects have been published in the past few years [1,2]. Single gene mutations were identified as heritable risk factors for atrial septal defects (ASD) in a number of patients (as reviewed by us in Posch et al [3]). Various mutations in transcription factors and sarcomeric genes were described in different studies [3].…”

“…Single gene mutations were identified as heritable risk factors for atrial septal defects (ASD) in a number of patients (as reviewed by us in Posch et al [3]). Various mutations in transcription factors and sarcomeric genes were described in different studies [3]. We have analyzed different genes involved in the pathogenesis of CHDs and could identify mutations in ASD patients [4,5,6].…”

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect

“…To date, the amount of genes related to CHD including ASD has been identified (Andersen et al, 2013): (1) transcription factors and co-factors, e.g., GATA4 (OMIM 600576), NKX2-5 (OMIM 600584), TBX5 (OMIM 601620), and TBX20 (OMIM 606061); (2) ligands-receptors, e.g., CRELD1 (OMIM 607170); (3) structure protein of sarcomere, e.g., MYH6 (OMIM 160710), MYH7 (OMIM 160760), and ACTC1 (OMIM 102540) (Posch et al, 2010b;Wessels and Willems, 2010;Ware and Jefferies, 2012;Andersen et al, 2013;Fahed et al, 2013).…”