Congenital heart disease and the role of genetics

Congenital heart disease is the most common malformation at birth, but what role do genetics play? Are all cases the same? In this blog we will explain congenital heart disease, its causes and detection methods.

What are congenital heart diseases?

Congenital heart disease (CHD) is defined as any malformation in the structure of the heart or major blood vessels, which, as the name suggests, are present from birth, even if they are diagnosed much later. This group of pathologies ranges from a single anomaly such as isolated valvular dysplasia to very complex lesions in which various defects coexist, as in the case of tetralogy of Fallot.

CHD originate during the prenatal period, specifically during embryonic development of the heart, between the 3rd and 10th week of gestation. The etiology of CHD in many cases is unknown, and it is generally accepted that the three main causes are: genetic alterations, external factors, or the combination of genetics and environment (multifactorial origin). Some of the external factors that may influence the development of CHD are maternal diabetes, alcohol or tobacco consumption, lupus, phenylketonuria or rubella during pregnancy.

Due to the diversity of congenital disorders that encompass CC, the complexity and severity of these conditions can vary significantly. Some patients may be asymptomatic, while others may have life-threatening conditions that require immediate intervention.

Each year more than one million children are born with congenital heart disease worldwide. The prevalence of CHD is estimated at 9 out of every 1,000 newborns, and can affect up to 14 out of every 1,000 pregnancies when fetuses from 18 weeks of gestation are taken into account. Thanks to improved screening and detection protocols, it is possible to establish early medical, pharmacological or surgical management, and it is estimated that more than 90% of newborns with CHD reach adulthood.

Throughout the article we will describe the different types of CHD, focusing on those of genetic origin.

Types of congenital heart disease

Congenital cardiopathies encompass a very broad group of malformations, although there are several types of established classifications, at a functional level they are considered:

• Cyanotic congenital heart diseases (Right-left short circuits) In these cases the passage of pulmonary blood to systemic blood occurs, so they are characterized by causing a decrease in blood oxygen levels (cyanosis), which leads to a bluish coloration of the skin and mucous membranes. Some of these heart diseases include transposition of great vessels, tetralogy of Fallot and Ebstein’s anomaly.
• Non-cyanotic congenital heart disease (left-right short-circuits) In these cases the passage of systemic blood to the pulmonary artery occurs, and includes defects in ventricular septal defect, atrial septal defect or atrioventricular septal defect, among others. 
• Congenital heart disease with obstructed blood flow. Obstructive lesions are usually caused by a narrowing of the blood vessels that hinders blood flow through the cardiac cavities, and include coarctation of the aorta or pulmonary stenosis, among other pathologies.

At the structural level they are usually divided into:

• Heterotaxia and transposition of great vessels (the heart and/or great arteries occupy anatomically different positions than normal).
• Conotruncal defects
• Left heart defects
• Defects of the right heartSeptal defects

At the causal level we distinguish:

• Multifactorial
• Chromosomal alterations
• Alterations in individual genes
• Alterations in the mitochondrial genome.

And at the clinical level we can consider two types of CC:

• Syndromic (associated with other clinical signs).
• Isolated

Once the types of CC classification have been described, we highlight some of the most frequent ones:

• Ventricular septal defect: there is continuity in the ventricular septum causing a shunt between the ventricles. Large defects cause a significant left-right shunt. In certain cases the defects may close spontaneously during lactation or require surgical intervention.
• Pulmonary stenosis: there is narrowing of the pulmonary outflow tract that obstructs blood flow from the right ventricle into the pulmonary artery during systole. This is an example of CHD that may remain asymptomatic until adulthood. Symptomatic patients are treated by balloon valvuloplasty.
• Tetralogy of Fallot: characterized by the presence of 4 simultaneous anomalies; large ventricular septal defect, right ventricular outflow tract obstruction, pulmonary valve stenosis, right ventricular hypertrophy and aortic ballooning. Definitive treatment is by surgery.

Screening for congenital heart defects

Currently, detection of congenital heart disease can be performed during pregnancy or during the first days after delivery. Early detection allows the initiation of treatment or the planning of medical or surgical interventions when necessary.

For prenatal detection, different techniques are available, including: 1) echocardiography, which provides detailed images of the heart using an ultrasound transducer; 2) specialized ultrasound or Doppler echocardiography, which allows assessment of blood flow; 3) analysis of specific biomarkers in maternal blood; and, in exceptional cases, 4) fetal magnetic resonance imaging, which allows more detailed images of the fetal heart to be obtained.

When congenital heart disease is suspected in a newborn, assessment of cardiovascular status by measuring blood pressure, peripheral perfusion and oxygen saturation with pulse oximetry is required. To confirm the diagnosis, Doppler echocardiography and an electrocardiogram are usually performed to rule out arrhythmias. Once the condition is confirmed, the most appropriate treatment is sought, which may vary in urgency depending on the defect and the patient’s condition.

For the detection of congenital heart disease in adults, techniques such as echocardiography, cardiac magnetic resonance imaging, computed tomography, cardiac catheterization, electrocardiogram and blood tests are used. These tests make it possible to evaluate the structure and function of the heart, detecting anomalies and cardiac problems that may have gone unnoticed.

Genetic causes of congenital heart disease

The genetic causes of congenital heart disease are very heterogeneous; today we know that behind CC of genetic origin there are deleterious germline or mosaic variants; structural and copy number variants; and variants in non-coding regions. Although it is true that in approximately half of the cases of CC a definitive cause is not established, thanks to technological and scientific advances it is now possible to identify genetic alterations in coding regions in approximately 45% of cases. It is important to note that the risk of recurrence in future pregnancies depends on the type of CC and the triggering factor. For this reason, it is always highly advisable to have professionals specialized in genetic counseling.

Approximately 13% of newborns with CC have other abnormalities and may develop neurodevelopmental delay during infancy. In these cases, when the additional findings are due to the same etiology, the CC is classified as syndromic. It is worth mentioning that the most frequent aneuploidies during pregnancy, Down syndrome (trisomy 21), Patau syndrome (trisomy 13) and Edwards syndrome (trisomy 18), as well as Turner syndrome (monosomy of the X chromosome) can present associated CC. In addition, some structural chromosomal abnormalities, such as microdeletion 22q11.2, commonly known as DiGeorge syndrome, can present conditions such as tetralogy of Fallot, interruption of the aortic arch, ventricular septal defect, among others.

On the other hand, the more widespread use of NGS sequencing in the study of CHD provides key information to better understand the causes and molecular mechanisms of this congenital anomaly. To date, more than 400 genes that contribute to CHD have been identified. We highlight several examples of CHD caused by variants in specific genes:

• Cardiopathies associated with Alagille syndrome: this is a complex disease that affects several organs such as the liver, brain or heart. At the cardiovascular level, Alagille syndrome can cause various CHDs such as tetralogy of Fallot, pulmonary stenosis and other symptoms. Autosomal dominant mutations in the JAG1 gene are identified in more than 90% of cases, while variants in the NOTCH2 gene are identified in 2%.
• Cardiopathies associated with Noonan syndrome: individuals with this condition have characteristic facial features. In 50-80% of cases they present with CHD, the most common being pulmonary stenosis. Several genes associated with the development of Noonan syndrome have been identified due to dominant gain-of-function mutations in genes such as PTPN11, SOS1, LZTR1, KRAS, RAF1, RIT1, SOS2, BRAF, MAP2K1, MRAS, NRAS, RRAS2, RASA2, among others.
• Cardiopathies associated with genes that regulate cardiac morphogenesis: genes such as NKX2-5 or TBX5, which are involved in the correct development of the sarcomere and cardiac contraction, so that alterations in these genes lead to failures during embryogenesis that can cause different CC such as arrhythmias or septal defect. The clearest example is Holt Oram syndrome, linked to mutations in TBX5.
• Signaling gene-associated heart disease: genes related to signaling pathways, such as Zic3, Nodal and Lefty2, can also cause congenital heart disease, such as Zic3-related X-linked visceral heterotaxia.

Detecting genetic causes of congenital heart disease

As more is known about the genetic contribution to congenital heart disease, the usefulness of genetic information to tailor patient management, stratify risk, establish prognosis, and counsel affected families is increasing. Although there is a lack of consensus on the type of test to implement in each case, specialized genetic testing is increasingly requested, as well as counseling by geneticists working together with pediatric cardiologists.

In the case of suspected CHD during pregnancy, the specialist will recommend performing an invasive procedure (amniocentesis or chorionic villus sampling) to obtain a sample of fetal tissue with which to perform molecular techniques to help obtain a diagnosis. Most commonly, a karyotype is performed initially to rule out or confirm the presence of chromosomal abnormalities such as Down syndrome or Turner syndrome. A more exhaustive molecular study may also be indicated to detect genetic alterations such as point variants or deletions and duplications (CNVs).

When a CC is identified after birth, depending on the case, the specialist may recommend a genetic study. Thanks to advances in the area of medical genetics, and the reduction in the cost of massive sequencing techniques, in many cases it will be possible to choose to perform whole exome sequencing for the study of CC, so it will always be helpful to have all the clinical information of the patient, which facilitates the interpretation by geneticists.

At Veritas, we prioritize the health of our patients by offering genetic screening and diagnostic services. We have specialists in various medical areas who can provide guidance on the most appropriate genetic test for each clinical case.

We have a wide portfolio of genetic tests based on whole exome and genome sequencing that provide key information to the specialist, with specific tests aimed at the diagnosis of congenital heart disease.