Commented article: Baban et al, 2022

Congenital heart defects (CHD) are the most common birth defect with an incidence of approximately 1%. One in ten will have an isolated atrial septal defect (ASD). Early diagnosis is usually secondary to an auscultation murmur that leads to ECHO.  Others are diagnosed later in life when symptoms of heart diseases appear. Despite closure of the defect, patients with an ASD have increased mortality and increased risk of atrial fibrillation, stroke, cognitive challenges, and psychiatric and neurodevelopmental challenges (Asschenfeldt 2020) - problems affecting multiple organs. These complications can only partly be explained by the haemodynamic changes caused by the ASD.  Patients with a non-familial ASD have increased burden of very rare gene variants, indicating that genetics contribute to the etiology of ASD (Nielsen et al. (2020)). 

ASD are seen in different syndromes and can occur in sporadic or familial cases. Genetic causes are mostly identified in syndromic or familial ASD as e.g., chromosomal changes, copy number variants, monogenic disorders, either inherited or de novo mutations. The familial monogenetic disorders often show diverse cardiac phenotypes.  

A review by Baban et al (2022) describes the link between variants in MYH7, NKX2.5, GATA4, TBX5 and TBX20 and CHD, heart muscle disease, and electrical disorders. This commentary provides a summary of the genes NKX2.5, GATA4 and TBX5.

Variants in transcription factor NKX2.5 are associated with ASD, conduction disease, arrhythmias, and sudden cardiac death. The variants are predominantly (94%) seen in familial cases and 15% of the patients experience sudden cardiac death before the age of 50 years (Ellesøe et al (2016)). 

GATA4 variants are identified in families with ASD. Variants in GATA4 are also known to cause ventricular septal defects, tetralogy of Fallot, atrioventricular septal defects and pulmonary valve stenosis.  ASD may occur concomitant with dilated cardiomyopathy, atrial fibrillation, and AV-block (Zhao et al (2014)) but in the majority of families with a GATA4 variant, ASD occur isolated with no other cardiac phenotypes.  

TBX5 variants are associated with CHD and ASD is the most common. Other cardiac abnormalities such AV-block, supraventricular arrhythmias, ventricular arrhythmias, and cardiomyopathies are associated, and, in most cases, upper-limb defects are also present, the so-called Holt-Oram syndrome. Though TBX5 variants most often are associated with Holt-Oram syndrome, isolated cardiac disease such as CHD, arrhythmias, cardiomyopathy, long QT syndrome, or sudden cardiac death can be seen with TBX5 variants.  

Transcription factor NKX2.5, GATA4 and TBX5 interact with each other and phenotypes of variants in these genes overlap.  

Though genetic causes are not always identified, Nielsen et al (2022) showed that having a familial ASD also leads to increased risk of atrial fibrillation and heart failure. Knowing that familial ASD patients have increased risk of severe cardiac morbidity hopefully encourage clinicians to follow patients with familial ASD closely even after successful repair. 

Overall, CHD is heterogeneous and CHD genes show overlapping phenotypes as many of the disease-causing genes interact in networks. A genetic cause is more likely identified in familial ASD compared to sporadic ASD and the known monogenic causes in ASD often co-occur with conduction disturbances, tachycardias or cardiomyopathy. Yet, the genetic understanding of ASD is still sparse and in sporadic ASD lacking.