Tetralogy of Fallot results from disturbed formation of the developing heart and great vessels during the first weeks of pregnancy, particularly the process by which a single outflow tract divides into the aorta and pulmonary artery. Most cases occur sporadically and reflect a multifactorial interplay of genetic and environmental factors that is not fully understood. Variants in GATA4, GATA6, JAG1, NKX2-5, TBX1, and ZFPM2 have been reported in individuals with tetralogy of Fallot or related conotruncal heart defects, and these genes participate in transcriptional and signaling programs that guide cardiac chamber and outflow tract development. GATA4 lies on chromosome 8, GATA6 on chromosome 18, JAG1 on chromosome 20, NKX2-5 on chromosome 5, TBX1 on chromosome 22, and ZFPM2 on chromosome 8. TBX1 is implicated through chromosome 22q11.2 deletions. When a familial pattern is recognized, inheritance is often described as autosomal dominant, meaning that a single altered copy of the gene can confer increased risk, although expression and severity can differ widely even within the same family. In many individuals, no specific genetic cause is identified.

Diagnosis relies on imaging of the heart together with careful clinical assessment. The condition is increasingly identified before birth through detailed fetal echocardiography. After birth, evaluation typically includes pulse oximetry screening, physical examination, electrocardiography, and chest imaging, followed by transthoracic echocardiography, which remains the cornerstone for confirming the four anatomical features and characterizing their severity. Cardiac magnetic resonance imaging and, in selected cases, cardiac catheterization may be used to define associated lesions such as pulmonary artery anatomy and coronary artery course. Because cyanosis and a heart murmur in a newborn can arise from several congenital heart defects, the symptoms can overlap with other conditions and detailed cardiac imaging is required to confirm the diagnosis. Genetic evaluation is offered to many infants and children with tetralogy of Fallot, particularly when extracardiac features or a family history of congenital heart disease are present. Chromosomal microarray is widely used to detect copy number variants such as 22q11.2 deletion, and targeted or broader gene panel testing may be considered when a syndromic or familial cause is suspected.

Care is multidisciplinary and centers on surgical repair of the heart, with medical therapy used to stabilize infants before surgery and to manage complications across the lifespan. In severely cyanotic newborns, prostaglandin E1 is used in specialized centers to maintain patency of the ductus arteriosus and preserve pulmonary blood flow until definitive intervention can be planned. When complete repair is not feasible early in life, a palliative procedure such as a systemic to pulmonary artery shunt may be performed to improve pulmonary blood flow as a bridge to later repair. Complete surgical repair, typically undertaken in the first months of life and often around three to six months of age, addresses the ventricular septal defect and relieves right ventricular outflow tract obstruction. There are no medications that correct the underlying anatomy. Long-term care includes management of residual lesions, arrhythmias, and pulmonary regurgitation, which is a common late consequence of outflow tract surgery. Pulmonary valve replacement, performed surgically or by catheter-based techniques, is often required in adolescence or adulthood, and implantable cardioverter defibrillators are considered in selected individuals at risk for ventricular arrhythmias. Regular surveillance is an essential part of long-term care and typically involves periodic cardiac imaging, electrocardiography, and arrhythmia assessment by a specialist in adult congenital heart disease.

Outcomes after surgical repair have improved substantially over recent decades, and most individuals who undergo timely repair in well-resourced centers now reach adulthood and lead active lives. Long-term survival depends on the severity of the original anatomy, the timing and completeness of repair, associated genetic or syndromic conditions, and adherence to lifelong cardiology follow-up. Late complications can include progressive pulmonary regurgitation, right ventricular dilation and dysfunction, arrhythmias, and a small but recognized risk of sudden cardiac events, which together drive the need for ongoing surveillance and timely re-intervention. Pregnancy, exercise participation, and noncardiac surgery require individualized assessment with an adult congenital heart disease team. Quality of life is generally good for many people with repaired tetralogy of Fallot, and outcomes continue to improve as surgical and catheter-based techniques advance.

Research efforts span surgical refinement, catheter-based pulmonary valve technologies, imaging methods, arrhythmia risk stratification, and genetic discovery. Several clinical trials are underway that evaluate aspects of perioperative care, long-term valve function, and outcomes in adults with repaired disease. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team to learn whether participation may be appropriate.