Genetic Testing for Congenital Heart Disease

Congenital heart disease (CHD) affects approximately 0.8% of live births and is the leading cause of non-infectious mortality during infancy. Heart development is a complex process influenced by multiple cellular interactions, genetic factors, and environmental influences. Even minor disruptions in this process can lead to structural heart abnormalities. Fortunately, scientific advancements have led to a clearer understanding of the genetic basis for certain congenital and hereditary heart conditions, making genetic testing—such as high-throughput sequencing and gene chip technology—an effective diagnostic tool.

Well-Understood Congenital Heart Conditions and Their Associated Genes

Several genes have been identified as playing a role in the development of congenital heart defects. For example, atrial septal defects (ASD) are associated with mutations in genes such as GATA4, MYH6, TBX20, ACTC1, TLL1, and NKX2-5. Ventricular septal defects (VSD) have been linked to CITED2, GATA6, CRELD1, GJA1, GATA4, and GATA6. Tetralogy of Fallot (TOF) is often associated with JAG1 and NKX2-5 gene mutations. Marfan syndrome, a connective tissue disorder often involving heart complications, is linked to FBN1 and FBN2. Other conditions, such as Wolf-Parkinson-White syndrome (WPW), are associated with the PRKAG2 gene. Hypertrophic cardiomyopathy is connected to genes like TNNT2, while dilated cardiomyopathy is linked to TNNI3. Long QT syndrome, a disorder affecting heart rhythm, is associated with mutations in KCNQ1, SCN5A, and KCNH2.

Genetic Syndromes with Associated Congenital Heart Defects

DiGeorge Syndrome and the TBX1 Gene

DiGeorge syndrome is one of the most common chromosomal deletion disorders, caused by a deletion in chromosome 22q11. It affects multiple organ systems, particularly the heart, due to abnormal migration of cardiac neural crest cells. Cardiac abnormalities may include aortic arch interruption, persistent truncus arteriosus, tetralogy of Fallot, double outlet right ventricle, and transposition of the great arteries. The TBX1 gene located in the 22q11 region is primarily responsible for the cardiac defects seen in DiGeorge syndrome, and mutations in this gene can also lead to the condition.

Holt-Oram Syndrome and the TBX5 Gene

Holt-Oram syndrome is characterized by both limb and heart abnormalities, earning it the alternate name of "heart-hand syndrome." Cardiac defects commonly include atrial septal defects (ASD), tetralogy of Fallot, and atrioventricular conduction block. Mutations in the TBX5 gene are responsible for this syndrome, and it was the first single-gene mutation identified in relation to cardiac septal defects. The clinical presentation of Holt-Oram syndrome can vary significantly, with some individuals experiencing severe heart defects and mild hand abnormalities, while others may show the reverse.

Char Syndrome and the TFAP2β Gene

Char syndrome involves both cardiac and hand anomalies. The hallmark heart defect is patent ductus arteriosus (PDA), often accompanied by minor hand malformations. Mutations in the TFAP2β gene disrupt the structure of its PY (protein domain) region, impairing its ability to bind DNA and ultimately leading to Char syndrome.

Noonan Syndrome and the PTPN11 Gene

Noonan syndrome, sometimes referred to as male Turner syndrome or female Turner-like syndrome, is characterized by distinctive facial features, chest deformities, and pulmonary valve stenosis. The PTPN11 gene is the primary causative gene for this condition. Other syndromes resembling Noonan syndrome include Cardio-Facio-Cutaneous syndrome, which is associated with mutations in MEK1/2, K-RAS, and B-RAF genes. Additionally, mutations in the H-RAS gene have been identified in patients with Costello syndrome, another condition with overlapping clinical features.