Congenital heart disease

Congenital heart defects are the most common birth defect, but what role does genetics play? Are all cases the same? In this blog, we'll explain congenital heart defects, their causes, and detection methods.

What are congenital heart defects?

Congenital heart disease (CC) is defined as any malformation in the structure of the heart or major blood vessels, which, as its name indicates, are present from birth, although 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.

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

The data

Due to the diversity of congenital disorders encompassed by congenital heart disease (CHD), the complexity and severity of these conditions can vary significantly. Some patients may be asymptomatic, while others may have life-threatening conditions requiring immediate intervention.

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

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

Types of congenital heart disease

Congenital heart defects encompass a very broad group of malformations, although there are several established classifications; at a functional level they are considered to be:

• Cyanotic congenital heart disease (Right-to-left shunts) In these cases, blood flows from the lungs into the systemic bloodstream. This is characterized by a decrease in blood oxygen levels (cyanosis), leading to a bluish discoloration of the skin and mucous membranes. Some examples of these heart conditions include transposition of the great arteries, tetralogy of Fallot, and Ebstein's anomaly.
• Non-cyanotic congenital heart disease (left-right shunts). In these cases, systemic blood passes into the pulmonary artery, and includes defects in ventricular septal defects, atrial septal defects, or atrioventricular septal defects, among others. 
• Congenital heart disease with obstruction of blood flow. Obstructive lesions are usually caused by a narrowing of the blood vessels that hinders blood flow through the heart chambers, and include coarctation of the aorta or pulmonary stenosis, among other pathologies.

At a structural level they are usually divided into:

• Heterotaxy and transposition of the great vessels (the heart and/or great arteries occupy positions anatomically different from normal).
• Conotruncal defects
• Left heart defects
• Right heart defects Septal defects

At the causal level we distinguish:

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

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

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

Having described the types of CC classification, we highlight some of the most frequent ones:

• Ventricular communication: There is continuity in the ventricular septum, causing a shunt between the ventricles. Large defects cause significant left-to-right shunting. In some cases, the defects may close spontaneously during infancy or require surgical intervention.
• Pulmonary stenosis: There is a narrowing of the pulmonary outflow tract that obstructs blood flow from the right ventricle to the pulmonary artery during systole. This is an example of coronary artery disease that can remain asymptomatic until adulthood. Symptomatic patients are treated with balloon valvuloplasty.
• Fallot Tetralogy: It is characterized by the presence of four simultaneous anomalies: a large ventricular septal defect, right ventricular outflow tract obstruction, pulmonic valve stenosis, right ventricular hypertrophy, and aortic bulging. The definitive treatment is surgery.

Detection of congenital heart defects

Currently, congenital heart defects can be detected during pregnancy or in the first few days after birth. Early detection allows for treatment to begin or for medical or surgical interventions to be planned when necessary.

For prenatal detection , Several 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 for the evaluation of blood flow; 3) analysis of specific biomarkers in maternal blood; and, in exceptional cases, 4) fetal magnetic resonance imaging, which allows for obtaining more detailed images of the fetal heart.

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

To detect 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 allow for the evaluation of the heart's structure and function, detecting abnormalities and heart problems that may have gone unnoticed.

Genetic causes of congenital heart disease.

The genetic causes of congenital heart disease are highly heterogeneous. Today we know that genetically related congenital heart defects include deleterious germline variants or mosaicism, structural and numerical copy number variants, and variants in non-coding regions. While it is true that a definitive cause is not established in approximately half of all congenital heart defects, 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 congenital heart defect and the triggering factor. For this reason, it is always highly recommended to consult with professionals specializing in genetic counseling.

Approximately 13% of newborns with CC have other abnormalities and may develop a delay in neurological development during childhood. 

In these cases, when the additional findings are due to the same etiology, congenital heart disease (CHD) 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 with associated CHD. Furthermore, some structural chromosomal abnormalities, such as the 22q11.2 microdeletion, commonly known as DiGeorge syndrome, can present with conditions such as tetralogy of Fallot, interrupted aortic arch, and ventricular septal defect, among others.

On the other hand, the more widespread use of NGS sequencing in the study of coronary artery disease provides key information for a better understanding of the molecular causes and mechanisms of this congenital anomaly. To date, more than 400 genes that contribute to coronary artery disease have been identified.

 We highlight several examples of coronary heart disease caused by variants in specific genes:

• Heart conditions associated with Alagille syndrome: This is a complex disease that affects several organs, including the liver, brain, and heart. Cardiovascularly, Alagille syndrome can cause various heart conditions 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 21%.
• Heart conditions associated with Noonan syndrome: Individuals with this condition have characteristic facial features. In 50-801 cases, congenital heart disease (CHD) is present, with pulmonary stenosis being the most common. Several genes have been identified as associated with the development of Noonan syndrome due to dominant gain-of-function mutations in genes such as PTPN11, SOS1, LZTR1, KRAS, RAF1, RIT1, SOS2, BRAF, MAP2K1, MRAS, NRAS, RRAS2, and RASA2, among others.
• Heart diseases associated with genes that regulate cardiac morphogenesis: Genes such as NKX2-5 and TBX5 are involved in the proper development of the sarcomere and cardiac contraction. Therefore, alterations in these genes cause defects during embryogenesis that can lead to various congenital heart defects, such as arrhythmias or septal defects. The clearest example is Holt-Oram syndrome, linked to mutations in TBX5.
• Heart disease associated with signaling genes: Genes related to signaling pathways, such as Zic3, Nodal, and Lefty2, can also cause congenital heart diseases, such as Zic3-related X-linked visceral heterotaxy.

Detection of genetic causes of congenital heart disease

As more is learned about the genetic contribution to congenital heart disease, the usefulness of genetic information increases in tailoring patient treatment, stratifying risk, establishing prognosis, and counseling affected families. Although there is no consensus on the type of test to implement in each case, there is an increasing demand for specialized genetic tests, as well as advice from geneticists in collaboration with pediatric cardiologists.

Pregnancy and hereditary conditions

If coronary artery disease is suspected during pregnancy, the specialist will recommend an invasive procedure (amniocentesis or chorionic villus sampling) to obtain a fetal tissue sample for molecular analysis to aid in 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 comprehensive molecular study may also be indicated to detect genetic alterations such as point variants or deletions and duplications (CNVs).

When a congenital heart defect (CHD) is identified after birth, depending on the case, the specialist may recommend a course of treatment. genetic study. Thanks to advances in the field of medical genetics, and the reduction in the cost of massive sequencing techniques, in many cases it will be possible to opt for whole exome sequencing for the study of cervical cancer. Therefore, it will always be helpful to have all the patient's clinical information, which facilitates interpretation by geneticists.

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

We have a broad 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.

Source: https://www.veritasint.com/blog/en/congenital-heart-disease-and-the-role-of-genetics/