In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

Commented article: Baban et al, 2022

Vibeke Elisabeth Hjortdal, Professor of Congenital Heart Surgery, MD, PhD, DMSc
Department of Cardiothoracic Surgery, Copenhagen University Hospital, Copenhagen, Denmark.

Anne Kathrine Møller Nielsen, MD, PhD fellow
Department of Cardiothoracic Surgery, Copenhagen University Hospital, Copenhagen, Denmark.

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.  



  • Asschenfeldt B, Evald L, Heiberg J, Salvig C, Østergaard L, Dalby RB, Eskildsen SF, Hjortdal VE. Neuropsychological Status and Structural Brain Imaging in Adults With Simple Congenital Heart Defects Closed in Childhood.  J Am Heart Assoc. 2020 Jun 2;9(11):e015843. doi: 10.1161/JAHA.120.015843. Epub 2020 May 19.PMID: 32427039  
  • Baban, Anwar, Valentina Lodato, Giovanni Parlapiano, and Fabrizio Drago. 2022. “Genetics in Congenital Heart Diseases: Unraveling the Link Between Cardiac Morphogenesis, Heart Muscle Disease, and Electrical Disorders.” Heart Failure Clinics 18(1):139–53. doi: 10.1016/j.hfc.2021.07.016. 
  • Ellesøe, Sabrina Gade, Morten Munk Johansen, Jesper Vandborg Bjerre, Vibeke Elisabeth Hjortdal, Søren Brunak, and Lars Allan Larsen. 2016. “Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature.” Congenital Heart Disease 11(3):283–90. doi: 10.1111/chd.12317. 
  • Ma, Ji Fang, Fan Yang, Saagar N. Mahida, Ling Zhao, Xiaomin Chen, Michael L. Zhang, Zhijun Sun, Yan Yao, Yi Xin Zhang, Gu Yan Zheng, Jie Dong, Ming Jun Feng, Rui Zhang, Jian Sun, Shuo Li, Qun Shan Wang, Huiqing Cao, Emelia J. Benjamin, Patrick T. Ellinor, Yi Gang Li, and Xiao Li Tian. 2016. “TBX5 Mutations Contribute to Early-Onset Atrial Fibrillation in Chinese and Caucasians.” Cardiovascular Research 109(3):442–50. doi: 10.1093/cvr/cvw003. 
  • Møller Nielsen, Anne Kathrine, Camilla Nyboe, Anne Sif Lund Ovesen, Sebastian Udholm, Malthe Mølgård Larsen, Vibeke E. Hjortdal, and Lars Allan Larsen. 2021. “Mutation Burden in Patients with Small Unrepaired Atrial Septal Defects.” International Journal of Cardiology Congenital Heart Disease 4(April):100164. doi: 10.1016/j.ijcchd.2021.100164. 
  • Nielsen, Anne Kathrine M., Sabrina Gade Ellesøe, Lars Allan Larsen, Vibeke Hjortdal, and Camilla Nyboe. 2022. “Comparison of Outcome in Patients With Familial Versus Spontaneous Atrial Septal Defect.” The American Journal of Cardiology 173:128–31. doi: 10.1016/J.AMJCARD.2022.02.047. 
  • Zhao, Lan, Jia Hong Xu, Wen Jun Xu, Hong Yu, Qian Wang, Hong Zhen Zheng, Wei Feng Jiang, Jin Fa Jiang, and Yi Qing Yang. 2014. “A Novel GATA4 Loss-of-Function Mutation Responsible for Familial Dilated Cardiomyopathy.” International Journal of Molecular Medicine 33(3):654–60. doi: 10.3892/IJMM.2013.1600. 
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.