Tetralogy of Fallot (Non-Syndromic)

Genetic architecture, the genetic assessment of patients with tetralogy, syndromic differential diagnosis, long-term outcomes and counselling

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Tetralogy of Fallot is the most frequent cyanotic congenital heart disease beyond the neonatal period and accounts for up to one tenth of all congenital cardiac lesions [2]. Anatomical description preceded its present name by more than two centuries: Steno in Denmark described it in 1673, and Arthur Fallot in Marseille coined “tetralogy” in 1888 when describing the lesions responsible for maladie bleue (blue disease) [2, 26]. Neill and Clark divided its history into four eras: pathological anatomy culminating in Maude Abbott's 1936 congenital heart disease atlas; clinical physiology and surgery, marked by the first Blalock–Taussig anastomosis in 1944 and open-heart surgery approximately ten years later; the infant era beginning in the mid-1970s with infant intracardiac repair, echocardiography and prostaglandins; and cardiac development from the 1990s, focusing on molecular mechanisms [26].

The fourth era brought the distinction organising this article. Approximately 20% have a recognised syndrome or chromosomal abnormality, led by 22q11.2 deletion, while 80% are non-syndromic without apparent Mendelian segregation and mostly without an identified cause [5, 6]. NKX2-5 transcription factor variants were first identified as a tetralogy cause [6]; an autosomal dominant, reduced-penetrance family due to a missense JAG1 variant followed in 2001 [27]. Exome sequencing of 829 non-syndromic patients identified NOTCH1 and FLT4 as the largest contributing loci, together in almost 7% [5], and a Canadian adult cohort extended the vascular endothelial growth factor (VEGF) pathway to KDR and other genes [8].

The distinction has practical clinical value. In newborns, 22q11.2 deletion changes surgical preparation, calcium and blood product management and counselling [7]. In childhood-operated adults, deletion often remains unrecognised — in 54% of Dutch adults with tetralogy or pulmonary atresia with VSD in whom it was identified, it was previously unknown [28] — and is associated with higher mortality [29]. In isolated disease, molecular diagnosis principally informs offspring risk and family assessment because malformation treatment is unchanged [4, 12].

Surgery transformed natural history: 25-year survival after simple repair was 94.5% in a large American cohort [18], and the adult population is growing. Follow-up does not end at repair because pulmonary regurgitation, ventricular dysfunction and arrhythmias determine adult morbidity and mortality [2, 16, 17]. This article addresses non-syndromic disease, genetic assessment of all tetralogy patients, long-term outcomes and counselling; congenital heart disease in general, 22q11.2 deletion and trisomy 21 are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Embryological and anatomical basis

The primary lesion is anterocephalad deviation of the ventricular outlet septum (infundibular septum), or its fibrous remnant when it has not muscularised [2]. This creates malalignment VSD and aortic override; tetralogy additionally requires abnormal morphology of septoparietal trabeculations surrounding the subpulmonary outlet, and the deviated septum combined with hypertrophied trabeculations produces RV outflow obstruction [2]. Septal deviation without subpulmonary obstruction is termed Eisenmenger VSD [2]. RV hypertrophy is the haemodynamic consequence of the other lesions [2]. The European Society of Cardiology (ESC) adds that aortic override is below 50% and obstruction may be infundibular, valvular, supravalvular and/or branch pulmonary arterial [17]. Bailliard and Anderson's Figure 1 shows a specimen with all four lesions (https://pmc.ncbi.nlm.nih.gov/articles/PMC2651859/figure/F1/) [2].

Physiologically, right outflow obstruction determines pulmonary flow, and interventricular pressure difference determines right-to-left shunting across the VSD, introducing deoxygenated blood systemically and causing cyanosis [6]. Muscular subpulmonary obstruction is dynamic, worsening with catecholamines or hypovolaemia and explaining hypercyanotic spells [2]. Chronic volume loading of the overriding aorta is implicated in adult aortic root dilatation [2].

2.2. Genetic architecture

Familial clustering supports a genetic component: in the Danish national study of 1,763,591 people born in 1977–2005, first-degree-relative recurrence risk ratio was 11.7 (95% confidence interval [CI] 8.0–17.0) for conotruncal defects including tetralogy and 48.6 (95% CI 27.5–85.6) for right outflow obstructions [30]. In a classical family study (Boon and colleagues, 1972, summarised in OMIM), heritability was approximately 54%, with sibling recurrence approximately 1% for tetralogy and 2% for any heart defect [3]. Nevertheless, Mendelian families are rare and most cases sporadic [5]; OMIM records apparently dominant transmission across three generations and a Lebanese Maronite sibship born to first cousins with tetralogy and pulmonary atresia, interpreted as potentially recessive [3]. The sources therefore describe a multifactorial architecture combining chromosomal abnormalities and recurrent CNVs (particularly 22q11.2), rare moderate- or high-effect variants with incomplete penetrance, oligogenic contributions of multiple rare variants within individuals and maternal environmental factors [5–7, 31]. Smith’s textbook adds that some reciprocal deletions and duplications (1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.3) associate with specific defects such as tetralogy with markedly low vertical-transmission penetrance and should be understood within a multifactorial model [32]. The AHA statement associates 1q21.1 duplication particularly with tetralogy, with GJA5 a possible causal interval gene [7]. According to OMIM, a study of 114 sporadic non-syndromic trios and a second cohort of 398 patients (Greenway and colleagues, 2009) identified 1q21.1 CNVs in 1% (5/512; OR 22.3) and estimated at least 10% (95% CI 4.5%–15.5%) of sporadic cases result from de novo CNVs, with recurrent CNVs also at 3p25.1, 7p21.3 and 22q11.2 and isolated CNVs spanning NOTCH1 and JAG1; a 148-family study (Lambrechts and colleagues, 2005) associated a common expression-reducing VEGF promoter haplotype (AAG) with increased risk (P=0.008), described as the first identified modifier gene [3].

In the largest published exome cohort (829 non-syndromic probands from UK, continental European and Australian centres), unique deleterious variants — absent from gnomAD with CADD ≥20 after excluding variants in 1252 reference exomes — clustered at genome-wide significance (P<5×10⁻⁸) in NOTCH1 and FLT4, without proband overlap [5]. When the nine highest-ranking genes were considered, 129 patients (more than 16%) had at least one unique deleterious variant, but this includes unvalidated candidates (RYR1, ZFPM1, CAMTA2, DLX6, PCM1) and should not be read as diagnostic yield [5].

2.3. Implicated genes, gene by gene

The cytobands given in the following paragraphs follow GeneGuidance [4].

NOTCH1 (9q34.3). This was the most frequent locus: 31 variants in 37 probands (4.5%; 95% CI 3.2%–6.1%), seven loss-of-function (three premature termination codons, three frameshifts and one deletion at a consensus splice site), 22 missense and two in-frame indels, distributed across the whole protein without clustering [5]. In seven probands with both parents available, five variants were de novo; the remainder were transmitted by unaffected parents, indicating incomplete penetrance [5]. Of the three functionally studied missense variants, p.(Cys607Tyr) reduced S1 cleavage (5% versus 57% in the wild type) and RBPJ-dependent signalling by 47%, and the de novo variant p.(Asn1875Ser) reduced this signalling by 38%; p.(Gly200Arg) did not alter signalling in vitro, but segregated with right-sided heart disease in an independent study (published protein designations, with no c. change given; the residues match the MANE protein NP_060087.3, transcript NM_017617.5) [5]. Germline NOTCH1 variants also cause Adams–Oliver syndrome, bicuspid aortic valve, aortic stenosis, coarctation and hypoplastic left heart, with no clear distinction in type or location between the variants of these phenotypes and those found in tetralogy [5].

FLT4 (5q35.3), VEGF receptor 3 (VEGFR3). In the cohort of 829 patients, 22 unique variants occurred in 21 probands (2.4%; 95% CI 1.6%–3.8%), 16 loss-of-function and six missense in immunoglobulin domains; no missense or in-frame variant fell in the kinase domain where Milroy disease variants occur [5]. Three were inherited from unaffected parents and one missense was de novo; a frameshift in two affected siblings came from their unaffected mother [5]. Page and colleagues cite an earlier 2871-proband congenital heart disease study finding FLT4 loss-of-function variants in 2.3% of 426 tetralogy patients [5]. Among 175 adults without 22q11.2 deletion of European ancestry, nine (5.1%) had novel FLT4 variants, seven loss-of-function including an 8 kb multiexon deletion [8]. GeneGuidance emphasises that there are two distinct autosomal dominant FLT4 phenotypes — Milroy disease (congenital lymphoedema, predominantly kinase-domain missense) and incompletely penetrant congenital heart disease, particularly tetralogy, through loss of function — which must be distinguished in the laboratory report [4].

Other VEGF pathway genes. In the Canadian cohort, ten further probands carried likely disruptive KDR (VEGFR2), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1 and PRDM1 variants; collectively VEGF pathway variants (19/175, 10.9%) associated with more absent pulmonary valve (26.3% versus 3.4%; P<0.0001) and right aortic arch (52.6% versus 29.1%; P=0.029), with rare extracardiac anomalies [8]. For KDR, GeneGuidance describes a 46-fold enrichment of truncating variants in 1569 European tetralogy patients, a family with two affected siblings and biallelic missense variants, and reduced VEGFR2 phosphorylation assays, but classifies the relationship as strong candidate rather than established, without ClinGen curation [4].

NKX2-5 (5q35.1). This was the first gene associated with tetralogy [6]. The principal phenotype of pathogenic variants is atrial septal defect (ASD) with atrioventricular conduction disturbance, but VSD, tetralogy, subaortic stenosis, pulmonary atresia and mitral valve anomalies are included [7]. Atrioventricular block is progressive and postnatal, so a repaired heart defect does not remove the risk; in a review of 202 patients, 15% of those with familial ASD and conduction disturbance died suddenly [4]. The book Clinical Cardiogenetics reports more than 50 NKX2-5 variants distributed across the functional domains in patients with ASD, VSD, hypoplastic left heart or tetralogy [33]. In the 829-proband cohort, unique variants in NKX2-5, GATA4, HAND2 and GATA6 explained only 1.2% of cases [5]. OMIM summarises earlier estimates: in 114 patients without 22q11 deletion, Goldmuntz and colleagues (2001) found four heterozygous NKX2-5 variants in six individuals, without conduction disease, with asymptomatic carriers in other families, and estimated the frequency at about 4% — but one of these variants (E21Q) was later reclassified as of uncertain significance; in 230 patients with tetralogy, Rauch and colleagues (2010) found the R25C variant, described as low-penetrance, in 0.9%, and in 178 Italian patients De Luca and colleagues (2011) found it in 1.1% [3]. A cautionary example is NM_004387.4(NKX2-5):c.73C>T, p.(Arg25Cys), described as the most recurrent NKX2-5 variant in congenital heart disease and associated with tetralogy in a Moroccan cohort [6]; in ClinVar it has conflicting classifications of pathogenicity (VCV000009008, March 2026 assessment) [34], and OMIM describes it as a low-penetrance variant, found by Benson and colleagues (1999) in a woman with tetralogy without atrioventricular block or ASD [3]; the description was confirmed on the MANE Select transcript with VariantValidator [35]. The conduction disease and cardiomyopathy associated with NKX2-5, as well as NKX2-5-related structural heart disease, are part of the differential diagnosis.

JAG1 (20p12.2). Eldadah and colleagues described a large autosomal dominant reduced-penetrance family caused by missense G274D (historical nomenclature): 9 of 11 carriers had heart disease — classical tetralogy with pulmonary stenosis, atresia or absent valve, VSD with aortic dextroposition and isolated peripheral pulmonary stenosis — and none met Alagille criteria although all had distinctive faces [27]. It corresponds to NM_000214.3(JAG1):c.821G>A, p.(Gly274Asp), at NC_000020.11:g.10652533C>T, normalised using VariantValidator [35]; ClinVar records likely pathogenic with one submitter, associated with Alagille syndrome (VCV000007624) [36]. Screening of 94 patients with tetralogy identified functionally relevant JAG1 variants in 2 (3%) without other syndromic signs [6]; in Rauch's 230 cohort, 3 (1.3%) had Alagille syndrome with JAG1 variants [3]. Smith’s textbook reports that JAG1 variants are identified in one third with only one or two Alagille features, predominantly cardiac (2% with tetralogy, 4% with peripheral pulmonary stenosis) [37].

Cardiac transcription factors and cofactors. Heterozygous GATA4 variants mainly cause ostium secundum ASD, but also VSD, pulmonary valve stenosis, atrioventricular septal defect (AVSD) and tetralogy; GATA6 is associated with truncus arteriosus, pulmonary stenosis, ASD and patent ductus arteriosus and, with inactivating de novo variants, with pancreatic agenesis with heart disease in 90% [7]. OMIM records GATA4 variants in 2 of 64 Chinese patients with tetralogy and missense GATA6 variants (p.(Leu198Val) and p.(Ser184Asn), published protein designations; the residues match the MANE protein NP_005248.2, transcript NM_005257.6) inherited from unaffected parents in patients with tetralogy, and ZFPM2 variants in 2 of 47 patients with sporadic tetralogy (Pizzuti and colleagues) and in 1 of 178 Italian patients [3]. GeneGuidance adds that GATA4 variants may cause neonatal or infantile diabetes and 46,XY testicular development abnormalities, and that heart disease is present in 83% of probands with GATA6 variants, whose diabetes may arise between the neonatal period and adulthood [4]. The same cardiogenetics book records GATA5 variants in tetralogy and de novo GATA6 variants with congenital heart disease, including tetralogy, in 92% of patients with pancreatic agenesis [33]. TBX1 is the main gene of 22q11.2-deletion heart disease; rare point variants occur in a small fraction of non-syndromic tetralogy, and ClinGen assigns isolated TBX1 a haploinsufficiency score of 1 (little evidence), so an isolated TBX1 deletion or truncating variant should not be presumed fully penetrant [4]. For ZFPM2 (FOG2), validity classifications for tetralogy vary between strong, moderate and limited depending on the GenCC submitter; for GDF1, the dominant form with tetralogy is disputed and a heterozygous variant should be treated, at most, as a susceptibility factor; for HAND2, the ClinGen expert panel assigned moderate evidence to HAND2-related heart disease in April 2026 [4]. Rare variants in TBX5, TBX20, FOXC1, FOXC2, FOXH1, CITED2, FLNA, NDRG4 and SMARCC2 have also been described in patients with tetralogy, largely with evidence from isolated cases or functional studies without independent replication [6, 7].

Cilia, regulation and oligogenicity: 2025–2026 data. Among 131 Han Chinese non-syndromic patients, rare loss-of-function ciliary variants were enriched; more than two deleterious variants had odds ratio (OR) 1.672 (95% CI 1.120–2.547), six variants cumulative OR 3.158 (95% CI 1.381–6.371), and single- and double-heterozygous mice reproduced tetralogy-like phenotypes with disrupted Hedgehog signalling [31]. Genome sequencing of 428 Chinese patients found TBX1-region findings in 9.81% (42/428), including 31 22q11.2 deletions and seven functional non-coding TBX1 enhancer variants (abstract data) [38]. These single-population research findings have not yet translated into clinical tests.

2.4. Environmental factors

The Oxford Desk Reference teratogen and maternal-disease table includes tetralogy among alcohol-associated defects (up to 25%–30% heart disease in fetal alcohol syndrome, predominantly VSD and ASD) and maternal phenylketonuria (approximately 15% heart disease, tetralogy and coarctation), and associates retinoids with conotruncal defects (10%–20%) [39]. Retinoid embryopathy includes tetralogy, transposition, VSD and ASD [40, 41], and poorly controlled maternal phenylketonuria includes congenital heart disease, particularly tetralogy and coarctation [42]. Untreated maternal diabetes is another reported association [2].

3. Clinical Spectrum and Manifestations by System

3.1. Anatomical spectrum

Each component varies in severity, determining presentation and treatment [2]. In four fifths of Caucasian patients the posteroinferior VSD margin is formed by aortic–tricuspid leaflet fibrous continuity (perimembranous defect), and in the remaining fifth it is muscular, protecting the conduction axis during closure; in a small proportion of Caucasians but more Far Eastern and Central and South American patients, the anterosuperior margin is aortic–pulmonary fibrous continuity (doubly committed defect) [2]. Bailliard and Anderson's Figures 2–4 illustrate these variants (https://pmc.ncbi.nlm.nih.gov/articles/PMC2651859/figure/F2/, https://pmc.ncbi.nlm.nih.gov/articles/PMC2651859/figure/F3/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC2651859/figure/F4/) [2].

More severe forms and relevant associations are summarised in Table 1. American College of Cardiology (ACC)/AHA 2025 guidance states that at least 15% born with tetralogy have pulmonary valve atresia, frequently requiring an RV–pulmonary artery conduit and lifelong replacements [16].

Table 1. Anatomical variants and associated lesions in tetralogy of Fallot

3.2. Cardiovascular manifestations before repair

Presentation depends on pulmonary flow obstruction severity [2, 14]. Most present neonatally with mild to moderate cyanosis, typically without respiratory distress; with mild initial obstruction, diagnosis may follow at two months with new cyanosis and louder murmur; pulmonary obstruction means no heart failure signs or poor weight gain [2]. The second heart sound may be single and loud, and a harsh systolic ejection murmur arises from obstructed outflow; the VSD generates no audible murmur, and more severe obstruction means more cyanosis and a softer murmur [2]. Clubbing is rare today because repair precedes it [2]. The Brazilian syndromes text describes neonatal cyanosis, tachypnoea, hyperpnoea, syncope, seizures, stroke and coma in severe forms, with lip and nail cyanosis, clubbing, palpable RV impulse and mid-left-sternal systolic thrill on examination [14].

A hypercyanotic spell is a sudden, marked fall in saturation due to acute, complete or near-complete obstruction of the subpulmonary outflow chamber [2]. Not all patients have them; they typically begin at around two months, at times of agitation or dehydration; during the spell the murmur disappears, the child becomes intensely cyanotic, hyperpnoeic and lethargic, and metabolic acidosis increases pulmonary and reduces systemic vascular resistance, with a risk of collapse and death [2]. The French PNDS describes the spell in more detail: it usually occurs in the morning, after a trigger (crying, pain, fear, exertion — in the infant, feeding itself —, fever, dehydration from gastroenteritis, an overheated environment or contraindicated drugs, such as diuretics, digoxin, positive inotropes and atropine); it begins with a hypertonic phase with agitation lasting a few seconds, followed by greyish pallor, hypotonia, grunting, reduced alertness, tachycardia, acidotic polypnoea and reduction or disappearance of the murmur; it lasts 15 to 30 minutes and carries a high lethal risk; the risk of a spell does not correlate with the degree of baseline cyanosis [11].

The same protocol distinguishes the presentation of the two variants it groups with tetralogy [11]. In tetralogy, an ejection murmur at the pulmonary area with isolated refractory cyanosis points to the diagnosis; neonatal cyanosis is usually mild and, when marked, indicates a narrow pulmonary pathway. In pulmonary atresia with ventricular septal defect, isolated refractory cyanosis occurs without a murmur or with a continuous murmur from the ductus arteriosus or MAPCAs; more rarely the cyanosis is mild and signs of heart failure from pulmonary overcirculation predominate. In absent pulmonary valve with VSD, bronchial compression by the dilated pulmonary arteries, on top of underlying bronchomalacia, causes respiratory distress, sometimes from the neonatal period; the shunt across the VSD is left-to-right, with heart failure, or right-to-left, with cyanosis, depending on the pulmonary obstruction, and auscultation reveals a systolic and diastolic murmur. Iron deficiency is common in the cyanotic infant, and a haemoglobin within the normal values for age already reflects relative anaemia in the face of the reactive polycythaemia of cyanosis [11].

3.3. Manifestations after repair and in adulthood

Significant pulmonary regurgitation is almost universal after transannular patch repair; tolerated for years, chronic severe regurgitation eventually causes RV dilatation and symptomatic dysfunction, worsened by distal stenosis or pulmonary hypertension [17]. Other sequelae include residual outflow obstruction, residual VSD, aortic dilatation and regurgitation (rarely dissection), tricuspid regurgitation, RV and left ventricular (LV) dysfunction, heart failure, atrial and ventricular arrhythmias, sudden death and endocarditis after pulmonary valve replacement [17]. LV dysfunction affects up to 20% of adults [16]. Estimated lifetime atrial arrhythmia prevalence is 20% [17], and a cross-sectional study of 556 adults (mean 36.8 years) found 43.3% had sustained arrhythmia or intervention, with atrial tachyarrhythmia in 20.1%, ventricular arrhythmias in 14.6% and marked increases in atrial fibrillation and ventricular arrhythmias after 45 [44]. Sustained monomorphic ventricular tachycardia mainly depends on slow-conducting anatomical isthmuses around right outflow [16, 17].

The adult ECG often shows complete RBBB dependent on surgical technique, with QRS duration influenced by RV dilatation [17]. Wide splitting of the second heart sound is common; a low-frequency early diastolic murmur suggests severe pulmonary regurgitation, a long loud systolic ejection murmur residual obstruction, a high-pitched diastolic murmur aortic regurgitation and a pansystolic murmur residual VSD [17].

3.4. Extracardiac manifestations and neurodevelopment

Non-syndromic forms by definition lack extracardiac malformations; these were rare in Canadian adults with VEGF variants [8]. Extracardiac anomalies, developmental delay or dysmorphism reclassify the patient as non-isolated tetralogy (TOF+) and change testing strategy (section 5) [13]. Irrespective of the genetic cause, neonatal cardiopulmonary bypass, bypass and intensive care duration and chronic cyanosis have associated with poorer neurological, motor and academic performance in some studies without randomised surgical strategy comparisons [2].

4. Clinical Recognition and Warning Signs

Recognition of tetralogy is a cardiological task, while recognition of its genetic context is the responsibility of the geneticist. The Oxford Desk Reference distinguishes five congenital heart disease settings: isolated; isolated with significant family history; syndromic; chromosomal; and teratogenic or maternal-disease-related [39]. Systematic 22q11.2 deletion testing is warranted because facial features evolve with age and clinical assessment alone does not consistently identify affected infants [7].

Cardiological warning signs. Echocardiography and clinical examination provide the first clues: neonatal cyanosis with systolic ejection murmur, boot-shaped radiographic silhouette (apical elevation from RV hypertrophy and concavity of hypoplastic pulmonary trunk) and ECG right axis deviation with RV hypertrophy that fails to normalise as in healthy newborns [2, 14]. Hypercyanotic spells mandate surgical referral [2]. During genetic assessment, anatomical markers of 22q11.2 deletion include arch abnormality (right, cervical or abnormal branching; OR 3.14 in tetralogy), pulmonary atresia (OR 2.03), discontinuous pulmonary branches and MAPCAs [2, 7, 43].

Extracardiac and familial warning signs. The Oxford Desk Reference recommends taking a three-generation family history focusing on heart disease and neonatal or infant deaths, twinning (approximately threefold risk in monozygotic twins), alcohol or medicine exposure (antiseizure medicines), chronic maternal disease (diabetes, phenylketonuria) and infection (rubella); examination includes growth parameters (noting cyanosis and heart failure may impair growth), Noonan-, Williams-, Turner-, 22q11.2- or trisomy-suggestive dysmorphism, nasal speech and submucous cleft, limb anomalies and cardiovascular examination of both parents [39]. The 2020 European consensus recommends genetic testing in any untested adolescent with a recognisable chromosomal phenotype or heart disease plus facial dysmorphism, skeletal defects, visceral malformations, growth or developmental delay, learning difficulties, behavioural or psychiatric disorders, or a family history of heart disease in one or more first-degree relatives, multiple miscarriages or siblings with congenital defects; tetralogy is among lesions increasing suspicion [12].

Table 2. Warning signs changing genetic assessment in tetralogy

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Anatomical diagnosis

Echocardiography establishes definitive diagnosis and usually supplies treatment-planning information: subpulmonary obstruction severity and dynamic component, pulmonary branch calibre, additional pulmonary flow sources, override, VSD size and associated lesions; catheterisation is rarely needed today [2]. Bailliard and Anderson's Figures 6–8 show characteristic echocardiographic views (https://pmc.ncbi.nlm.nih.gov/articles/PMC2651859/figure/F6/) [2]. ECG and radiography complete initial assessment (section 4), and CT angiography and magnetic resonance have replaced catheterisation for anatomical definition [14]. In repaired adults, cardiac magnetic resonance (CMR) is the reference for ventricular volumes and function, regurgitation, flows and fibrosis (late gadolinium enhancement); cardiac computed tomography (CT) defines coronaries and outflow relationships, conduit calcification and MAPCAs; cardiopulmonary exercise testing, Holter and electrophysiological study are used selectively; catheterisation is reserved for intervention or unresolved non-invasive questions [16, 17].

The French PNDS describes the neonatal pathway starting from cyanosis [11]. Without a prenatal diagnosis, any neonatal cyanosis, especially if isolated, should raise suspicion of a potentially duct-dependent cyanotic heart defect, which justifies looking for cyanosis or hypoxaemia in all newborns; in case of clinical doubt, pulse oximetry has adequate predictive value for screening these heart defects in asymptomatic newborns. The hyperoxia test measures saturation and, above all, arterial partial pressure of oxygen (PaO2) in room air and under 100% oxygen: absent or weak rise in saturation, or PaO2 below 150 mmHg under 100% oxygen, define refractory cyanosis and lead to urgent echocardiography. The radiograph shows a “boot-shaped” heart (sabot) with clear lung fields in tetralogy and pulmonary atresia, and signs of bronchial compression (atelectasis) in absent pulmonary valve. Doppler echocardiography should document additional muscular VSDs, the diameter of the pulmonary annulus and valve stenosis, the confluence and calibre of the pulmonary branches, the ductus arteriosus, coronary anomalies with surgical impact (coronary artery crossing in front of the right ventricular outflow chamber, anterior descending artery arising from the right coronary artery, dual anterior descending artery) and the position of the aortic arch relative to the trachea. In pulmonary atresia with ventricular septal defect, CT angiography or MR angiography are almost systematic for the pulmonary tree, the MAPCAs and their bronchial relationships, and catheterisation measures pressures in the MAPCAs and native arteries and shows the communications between them, possibly requiring several examinations because of the contrast limit and being repeated to follow the growth of the pulmonary tree or to embolise MAPCAs; in absent pulmonary valve, CT and fibreoptic bronchoscopy quantify airway compression. Severity is assessed by tolerance (degree of cyanosis, spells, respiratory distress and blood gases), duct dependence, pulmonary and coronary anatomy, multiple VSDs, bronchomalacia, associated malformations, prematurity, growth restriction, maternal–fetal infection and the presence of a genetic syndrome [11].

5.2. Prenatal diagnosis

Tetralogy can be diagnosed from 12 weeks of gestation, but in a population study only half of cases were detected on routine obstetric ultrasound; fetuses referred for fetal echocardiography tend to have the more severe phenotypes and worse outcomes than those diagnosed after birth [2]. The AHA statement suggests testing for 22q11.2 deletion in all fetuses with tetralogy when diagnostic amniocentesis is performed [7], and GeneReviews states that ultrasound identification of conotruncal anomalies, including tetralogy, in a pregnancy without known familial risk may suggest the deletion, to be confirmed by microarray, MLPA (multiplex ligation-dependent probe amplification) or FISH (fluorescence in situ hybridisation) in fetal cells [46]. When amniocentesis is performed for an ultrasound anomaly, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend prenatal CMA, according to the AHA statement [7]. Vaginal delivery is possible but should take place at a centre with paediatric cardiology [2]. The French PNDS organises in utero transfer to the reference centre, a competence centre or a facility linked to them, and defines the level of the maternity unit: level II or III for tetralogy and level III for pulmonary atresia with ventricular septal defect and for absent pulmonary valve, followed by early specialist consultation; in pulmonary atresia, the newborn is admitted to the centre from birth, to assess duct dependence [11]. The same protocol systematically proposes microdeletion testing when the diagnosis is prenatal, in agreement with the AHA [7, 11].

5.3. Genetic tests: indications and yield

The genetic assessment rests on two observations: 22q11.2 deletion is frequent and not always recognisable clinically, and non-syndromic disease has low molecular diagnostic yield distributed across many genes [5, 7]. The AHA considers 22q11.2 deletion testing reasonable in all tetralogy patients — fetuses undergoing amniocentesis, newborns, children, adolescents and adults — recommending CMA [7]. The Oxford Desk Reference notes urgent analysis (chromosomes with 22q11 FISH) may be needed in sick newborns for prognostic and surgical implications and recommends DNA storage before open-heart surgery or extracorporeal membrane oxygenation (ECMO) [39]. The European consensus places CMA as the first-line test, especially in syndromic disease, to detect aneuploidies and CNVs (≥25 kb), notes exome sequencing is becoming principal for single nucleotide variants with virtual panels, and suggests trio genome sequencing for severe syndromic or isolated cases undiagnosed after CMA and exome [12]. ESC 2020 recommends considering counselling with or without testing in all adults with congenital heart disease [17].

The 2008 French PNDS adopts a more selective strategy, predating the widespread use of CMA [11]. It proposes FISH for the 22q11 microdeletion, at any age, when tetralogy (of any form), pulmonary atresia with ventricular septal defect or absent pulmonary valve is associated with at least one extracardiac sign of the syndrome; it arranges a genetics clinic appointment in the presence of multiple congenital anomalies, dysmorphism, intellectual disability or a normal karyotype with persistent suspicion; it performs cytogenetic testing if the phenotype corresponds to a known syndrome, if there is intellectual disability, multiple anomalies, growth delay not explained by the heart defect or a family history; and it places the genetics clinic appointment before cytogenetic testing. Signs raising a syndromic hypothesis are sought on examination (dysmorphism, limb anomalies), on chest radiography (skeletal anomalies) and, when there are pointers, on abdominopelvic ultrasound, transfontanellar ultrasound and brain MRI [11]. The divergence from later sources is twofold: the 2018 AHA statement considers it reasonable to test all patients with tetralogy, with or without extracardiac signs, because the face may be subtle in infancy, and the European consensus and the AHA prefer CMA to FISH, which only detects deletions that include the probe and does not identify other CNVs [7, 12, 46].

Yield data are summarised in Table 3. Among symptomatic newborns requiring neonatal intervention (572 patients, nine US centres, 2005–2017), 26.4% had a genetic diagnosis in hospital records, of which 41.7% were 22q11.2 deletion, 18.5% trisomy 21 and 39.7% others [48]. In non-isolated tetralogy (TOF+), clinical exome after non-diagnostic CMA provided definitive or probable diagnosis in 23.6% (31/131); commercial congenital-heart-disease panels would identify only 27.3%–63.6% of these, and authors conclude exome should be considered in all TOF+ patients undiagnosed by CMA, whose tetralogy yield they cite as 10%–20% [13]. The study also proposes tetralogy as a low-penetrance phenotype of pathogenic DVL3, MED13L, PUF60 and MEIS2 syndromes [13].

Table 3. Genetic testing yield in tetralogy cohorts

Values are not directly comparable because selection (tertiary centre, population, adult survivors, symptomatic disease, TOF+), techniques and positivity criteria differ. “Unique deleterious” research frequencies measure rare variant enrichment, not the proportion with a molecular diagnosis under American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria [5, 8].

5.4. Source-based proposed algorithm

1. Confirm anatomy (echocardiography; CMR or CT by age and clinical question) and record 22q11.2 markers: arch, pulmonary atresia, MAPCAs, discontinuous branches [2, 7, 43].
2. Obtain three-generation history, seek teratogens and maternal disease, examine patient and both parents [39].
3. CMA in all patients with tetralogy, urgently in the newborn who is to undergo surgery; store DNA before surgery [7, 39]. In a patient with a trisomy phenotype, karyotype to distinguish free trisomy from translocation.
4. A normal CMA with TOF+ (extracardiac malformations, developmental delay, dysmorphism): preferably trio exome; consider trio genome if non-diagnostic [12, 13].
5. A normal CMA and isolated tetralogy with familial conotruncal or right outflow heart disease or a specific-gene-suggestive phenotype (absent pulmonary valve or right arch; neonatal diabetes; AV block; Alagille features): exome or broad panel analysing NOTCH1, FLT4, KDR, JAG1, NKX2-5, GATA4, GATA6 and TBX1, recognising commercial panels may omit relevant genes [4, 5, 8, 13].
6. Sporadic isolated tetralogy with normal CMA: expected additional yield is low; use shared decisions and empirical counselling risks (section 8) [5, 7].
7. Never-tested adult: offer 22q11.2 deletion testing, particularly before pregnancy [17, 28].

Steps 1–3 and 7 reflect explicit recommendations; steps 4–6 synthesise recommendations and yield data rather than a society-published algorithm.

5.5. Test limitations and report contents

Conventional G-banded karyotype misses recurrent 22q11.2 deletion [46]. LCR22A–LCR22B FISH misses deletions outside that region; approximately 85% have the 2.54 Mb A–D deletion (historically 3 Mb), approximately 5% the 1.5 Mb A–B, approximately 2% A–C and approximately 5% smaller B–D or C–D deletions [46, 49]. CMA misses inversions and balanced translocations [12]. Exome sequencing has limited coverage of non-coding regions, with the 2026 TBX1 enhancer example demonstrating genome-accessible regulatory variation still under research [38]. A negative test does not exclude a genetic cause, and incomplete penetrance in NOTCH1, FLT4 and JAG1 means an unaffected parental carrier neither makes a variant benign nor proves pathogenicity [5, 27]. Partial segregation or isolated functional studies do not establish that a variant of uncertain significance is pathogenic.

The report should state the gene, the versioned transcript (e.g. NM_004387.4 for NKX2-5, NM_000214.3 for JAG1 and NM_182925.5 for FLT4, MANE Select transcripts confirmed using VariantValidator), normalised HGVS nomenclature (Human Genome Variation Society), zygosity, ACMG/AMP classification and limitations; historical nomenclature (JAG1 G274D) or earlier transcripts (FLT4 NM_182925.4) should be included alongside current forms [8, 27, 35]. For FLT4, distinguish cardiac from Milroy phenotype [4].

6. Differential Diagnosis

6.1. Cardiological differential

In cyanotic newborns with murmurs, consider persistent pulmonary hypertension and other cyanotic lesions: critical pulmonary stenosis, Ebstein malformation, transposition, common arterial trunk, total anomalous pulmonary venous drainage and tricuspid atresia [2]. Fallot-type double-outlet RV and pulmonary atresia with VSD share the outlet septal deviation spectrum; ESC treats the latter separately in adults, sharing intracardiac anatomy but without direct RV–pulmonary artery communication [2, 17].

6.2. Aetiological differential: syndromic and teratogenic forms

Approximately 20% have a syndrome or chromosomal abnormality [6, 17]; up to one eighth have trisomy 21, 18 or 13, and up to one fifth with tetralogy and pulmonary stenosis and two fifths with pulmonary atresia have 22q11.2 deletion [2]. ESC lists 22q11 microdeletion, trisomy 21 and Alagille, Noonan, Williams and Klippel–Feil syndromes [17]. Table 4 assembles conditions with source-described tetralogy and distinguishing features.

Table 4. Aetiological differential diagnosis of tetralogy of Fallot

6.3. Distinguishing features of practical interest

22q11.2 deletion and Alagille distinction matters because they share tetralogy, VSD, butterfly vertebrae and poor weight gain; liver disease is not part of 22q11.2 deletion and genetics distinguishes them [47]. A clinical diagnosis of Alagille syndrome requires bile duct paucity and three of five major criteria (cholestasis, heart disease, butterfly vertebrae, posterior embryotoxon, characteristic face), or one major criterion with family history; pathogenic JAG1 or NOTCH2 establishes molecular diagnosis, uncertain variants neither establish nor exclude it [47]. Eldadah's family shows JAG1 may cause familial tetralogy without Alagille criteria [27], placing JAG1 among both syndromic differentials and isolated-form genes. Similarly NOTCH1 (isolated tetralogy and Adams–Oliver) and FLT4 (tetralogy and Milroy) phenotypes tend to occur separately [4, 5].

Non-isolated tetralogy (TOF+) has the highest diagnostic yield from exome sequencing, and sources indicate extracardiac anomalies or neurodevelopmental disorders should prompt full genomic investigation [12, 13]. Absence of infant dysmorphism does not exclude 22q11.2 deletion because the face may become evident later [7].

7. Treatments and Risk Management Strategies

7.1. Principles

No treatment targets tetralogy's genetic cause. Treatment addresses the malformation according to general congenital heart practice; genetics mainly changes surveillance, perioperative preparation and counselling [4, 7]. Surgery is indicated in all cases, complete or palliative, and therapeutic catheterisation with ductal or RV outflow stenting is an alternative to palliative surgery [14].

7.2. Neonatal period and hypercyanotic spells

Depending on subpulmonary obstruction, prostaglandin infusion may maintain ductal patency and stable pulmonary flow; those requiring infusion will probably undergo surgery before discharge, whereas adequate antegrade flow after duct closure allows follow-up until complete repair [2]. Alprostadil (prostaglandin E1) has a labelled indication, with dosing in Table 5.

Table 5. Medicine with a labelled indication in duct-dependent neonatal tetralogy

The French PNDS adds its own dosing to that of the label [11]. Prostaglandin E1 is indicated, in hospital at the reference or competence centre, in duct-dependent forms; when a duct-dependent heart defect is suspected in a newborn far from an experienced centre, it may be started before the diagnosis is confirmed, in agreement with the centre. The proposed starting dose is 0.01 to 0.025 µg/kg/min (the protocol uses the old unit “gamma”, equivalent to the microgram), seeking the lowest dose that keeps the ductus open with fewer adverse effects; maintenance doses of 0.001 µg/kg/min are sometimes sufficient, and the protocol sets no maximum dose (the label allows up to 0.4 µg/kg/min). The adverse effects listed are hyperthermia, cutaneous flushing, apnoeas and bradycardias, seizures and necrotising enterocolitis, whose risk increases with prematurity, doses above 0.05 µg/kg/min, episodes of low cardiac output or shock, severe hypoxia and an umbilical catheter; cardiorespiratory monitoring and monitoring of gastric residuals are essential, and assisted ventilation and suspension of enteral feeding are sometimes needed. When cyanosis is poorly tolerated, symptomatic treatment includes assisted ventilation without seeking to raise saturation or PaO2, good-quality venous access and correction of electrolyte, acid–base and haemodynamic disturbances. The PNDS starting dose is lower than that of the US label and the Portuguese SmPC (0.05 to 0.1 µg/kg/min); the guideline dose prevails as the reference and the label dose serves for comparison, and the two sources agree on reducing the infusion to the lowest effective dose [11, 15, 61].

In a hypercyanotic spell, the aim is to reduce pulmonary vascular resistance and increase systemic resistance, favouring left-to-right flow across the VSD and flow into the outflow chamber [2]. Parents learn to place the child in the knee-to-chest position and to call the emergency services; in hospital, the approach described by Bailliard and Anderson includes intravenous access with fluids, oxygen, subcutaneous morphine to reduce catecholamine release and, if the spell persists, sedation with muscle relaxation, intubation and intravenous phenylephrine to increase systemic resistance [2]. According to these authors, the long half-life and adverse effects of beta-blockers (hypotension, cardiac dysfunction) argue against their routine use in the emergency; propranolol has been used at low doses to prevent spells, but the need for prophylaxis should prompt surgical referral [2]. Bailliard and Anderson do not give doses; the French PNDS gives them and is the dosing reference of this article (Table 6) [11]. At home, the immediate action is to fold the child's knees onto the chest, to increase systemic resistance and force flow through the pulmonary pathway, contact the paediatric cardiology department and transport the child, via the emergency medical service, to the nearest hospital agreed with the centre. In hospital, the protocol starts by clearing the airway, ventilating if necessary with a fraction of inspired oxygen of 100% and keeping the knees on the chest; in the hypertonic phase, it sedates the child with rectal diazepam or with intravenous or intramuscular morphine (0.1 mg/kg as a single dose, with no maximum or repetition defined in the protocol) in the absence of venous access; it treats acidosis with intravenous bicarbonate and gives boluses of normal saline of 5 to 10 mL/kg to increase pulmonary flow; without rapid recovery, it slowly injects intravenous propranolol diluted to 1 mg/mL (5 mg in 5 mL of 5% glucose), under monitoring, until the heart rate falls below 130/min and the murmur reappears; if the spell persists, it increases systemic resistance with an alpha agonist (phenylephrine or noradrenaline by continuous infusion), beta-adrenergic stimulation being formally contraindicated. While awaiting surgery, the PNDS allows, in the infant, oral propranolol at 3 mg/kg/day outside the terms of the marketing authorisation, with no maximum defined (maintenance in the infantile haemangioma labels is 3 to 3.4 mg/kg/day), and considers the surgical indication urgent or semi-urgent after a spell [11].

The two sources diverge on three points. The route for morphine is subcutaneous in Bailliard and Anderson and intravenous or intramuscular in the PNDS [2, 11]. Intravenous propranolol is a step of the French protocol for the spell that does not resolve, whereas the review by Bailliard and Anderson advises against routine beta-blockers in the emergency [2, 11]. Noradrenaline appears in the PNDS with the unit “0.05 to 0.1 mg/kg/min”, a thousand times above the order of magnitude of catecholamine infusions expressed in µg/kg/min; this is a unit error in the document, which must not be transcribed, and the dose to use is that of the centre protocol, with the adult label as comparison [11, 62]. The hypercyanotic spell is not among the labelled indications of any of these drugs, and none of the labels consulted establishes a paediatric dose for these indications; the label doses in Table 6 are for adults or for another paediatric indication and serve for comparison, and use in the infant with tetralogy is off-label use. Extrapolation of the infantile haemangioma dose to the prevention of hypercyanotic spells is off-label use, not validated in tetralogy. As a paediatric comparison, the cyanotic spell protocol of the East Midlands Congenital Heart Centre and Leicester Children's Hospital (version 5, approved in September 2023) uses morphine at 50 µg/kg (SC, IV or IM, repeatable once), normal saline boluses of 10 mL/kg and, in the absence of a regular beta-blocker, oral propranolol 0.5 mg/kg 3 times daily, up to 1 mg/kg 3 times daily. It does not use IV propranolol, which it considers unavailable. Intravenously it uses esmolol below 2 months (600 µg/kg over 1–2 min, up to 3 doses, followed by an infusion of 300–900 µg/kg/min) or metoprolol from 2 months (100 µg/kg over 5 min, maximum 5 mg per dose, up to 3 doses, followed by an infusion of 1–2 µg/kg/min). Phenylephrine is given as an IV bolus of 5–10 µg/kg over 3–5 min, repeatable every 20 min, and an infusion is only considered at the intubation stage in intensive care [63]. The morphine in this protocol is half the PNDS dose, and phenylephrine is used as boluses, whereas the PNDS gives it by continuous infusion.

Table 6. French PNDS dosing in the hypercyanotic spell and in the preoperative period, with the labels as comparison

7.3. Surgical repair

Palliation, often avoiding bypass, creates reliable pulmonary flow through a prosthetic systemic–pulmonary arterial conduit, usually modified Blalock–Taussig shunt (subclavian to ipsilateral pulmonary artery); complete repair always uses bypass, patches the VSD to direct LV output to aorta, relieves subpulmonary obstruction and reconstructs pulmonary arteries if needed [2]. Centres divide between neonatal complete repair and neonatal palliation with repair at 4–6 months; perioperative mortality is below 3% for both and neither has proven superiority without randomised trials [2]. Neonatal repair relieves RV load and cyanosis earlier but exposes the neonatal brain to bypass and increases transannular patch likelihood with chronic pulmonary regurgitation, adult exercise intolerance and arrhythmia [2]. Pulmonary valve preservation is now preferred whenever possible [16].

The French PNDS organises the options by anatomical form and reserves all surgery, at any age, for congenital heart surgeons, and percutaneous procedures for interventional cardiologists in the same field [11]. In duct-dependent or poorly tolerated tetralogy (severe cyanosis or spells), the options are a systemic-to-pulmonary shunt (the most frequent), neonatal repair, enlargement of the RV–pulmonary artery pathway without VSD closure and, more rarely, ductal stenting or percutaneous valvuloplasty. In non-severe forms, repair is performed from the third month and may be deferred: VSD closure, opening of the pulmonary pathway with a patch, with or without opening of the annulus depending on its calibre, and ligation of shunts or the ductus arteriosus; an anterior descending artery arising from the right coronary artery or a dual anterior descending artery may require an extracardiac RV–pulmonary artery conduit. In duct-dependent pulmonary atresia with ventricular septal defect, palliation may include a systemic-to-pulmonary shunt, re-establishment of RV–pulmonary artery continuity without VSD closure (restrictive conduit or biological tissue, such as left atrial appendage or a pericardial flap), unifocalisation of the pulmonary arteries and collaterals, embolisation of MAPCAs, dilatation of pulmonary stenoses and, more rarely, ductal stenting or perforation of the valve plate; repair, in one or several surgical or percutaneous stages, seeks to obtain a pulmonary arborisation compatible with complete repair; without duct dependence, there is no treatment and the onset of cyanosis or heart failure is monitored. In absent pulmonary valve with VSD, treatment is always repair: VSD closure with arterioplasty of the pulmonary arteries and/or the Lecompte manoeuvre (translocation of the pulmonary artery in front of the aorta), with or without a valved RV–pulmonary artery conduit; before surgery, respiratory distress is treated with prone positioning with head elevation and ventilatory support, and after it residual airway compression may require prolonged ventilation, reintervention (suspension or reduction plasty of the pulmonary arteries, lobectomy) or a bronchial stent, because bronchomalacia persists [11].

Repair in adulthood is rare, because almost all adults have already been operated on; some reach adulthood with palliation only (classic or modified Blalock–Taussig shunt, Waterston shunt between the ascending aorta and right pulmonary artery, Potts shunt between the descending aorta and left pulmonary artery, Brock operation or pulmonary valvotomy, or an RV–pulmonary artery conduit without closure or with fenestration of the VSD) [11]. The PNDS reports an early mortality of 15.4% for repair in adults, with marked preoperative cyanosis (raised haemoglobin) as a probable risk factor, and weighs the indication according to symptoms and functional class, the patient's choice, surgical difficulty, organ dysfunction, the degree of cyanosis and the haematocrit, the risk of postoperative ventricular dysfunction and pulmonary resistance; before surgical correction, coronary angiography is systematic in men over 40 years, in women over 50 years or in the presence of cardiovascular risk factors [11].

In 3283 Americans surviving simple tetralogy repair in 1982–2003, staged repair (HR 2.68; 95% CI 1.59–4.49) and non-valve-sparing surgery (HR 3.76; 95% CI 1.53–9.19) associated with greater early (<6 years) but not late mortality; genetic abnormalities associated with higher mortality in both phases (HR 3.64 and 4.41) [18]. These observational data reflect selection and cannot establish technique causality.

Among 572 symptomatic newborns at nine American centres (230 primary repairs, 342 staged), 52 (9%) died at median 82 days; Of the deaths, 52% occurred perioperatively (within 30 days) and 69% were from cardiac causes (mainly heart failure and sudden death), and associated factors were prematurity, low weight, genetic syndrome, extracardiac anomaly and preintervention ventilation [71]. In the same cohort, a genetic diagnosis did not significantly increase adjusted death risk (adjusted HR 1.71; 95% CI 0.96–3.07; P=0.07) but associated with longer intensive care (13 versus 9 days) and hospital stays (32.5 versus 24 days) and more feeding-tube discharge (OR 2.1) [48]. In a Philadelphia series (208 patients, 1995–2006), 22q11.2 deletion patients had more prerepair shunts (21% versus 7%), longer bypass and intensive care (6 versus 4 days), without survival difference [72].

7.4. Genotype-guided management

Table 7. Management implications of frequent genetic diagnoses in the patient with tetralogy

7.5. Adult interventions after repair

Pulmonary valve replacement and relief of outflow obstruction are performed with low mortality in the absence of heart failure or advanced ventricular dysfunction, and longitudinal data carry more weight than isolated measurements in the decision [17]. The two current guidelines diverge on the volumetric criteria for the asymptomatic patient (Table 8). The 2025 ACC/AHA guidance is now based on indexed RV end-systolic volume (>80 mL/m²) and other parameters, rather than end-diastolic volume, because these correlate better with outcomes [16]; ESC 2020 retains indexed end-diastolic volume ≥160 mL/m² alongside end-systolic ≥80 mL/m², noting that RV normalisation becomes unlikely above these values but that the threshold may not correspond to clinical benefit [17].

Table 8. Recommendations of the American (ACC/AHA/HRS/ISACHD/SCAI 2025) and European (ESC 2020) guidelines for the adult with repaired tetralogy

*ACC/AHA defines pulmonary dysfunction as moderate regurgitation or RV systolic pressure above 2/3 systemic from outflow obstruction. Moderate regurgitation definition is inconsistent: the recommendation footnote requires CMR regurgitant fraction “>25%”, while synopsis (“at least 25%”) and Figure 6 legend (“≥25%”) use ≥25%; exactly 25% is classified differently by passage [16]. ACC/AHA sustained ventricular tachycardia/sudden death factors: QRS ≥180 ms, at least moderate LV/RV dysfunction, previous ventriculotomy, late repair, symptomatic non-sustained ventricular tachycardia or arrhythmic symptoms, QRS fragmentation and inducible sustained ventricular tachycardia (table 32); ablation reduced appropriate ICD therapies (10% versus 37% in one series; HR 0.13 in another), and pre-emptive electrophysiology before replacement yielded actionable findings in approximately 25%; primary-prevention ICD associates with frequent inappropriate shocks without randomised benefit trials [16]. ACC/AHA has 16 tetralogy recommendations (5 class 1, 6 class 2a and 5 class 2b; none class 3), all B-NR, C-LD or C-EO, without randomised trials [16]; ESC recommendations are all level C [17]. Classes were read in official recommendation table images.

7.6. Medical treatment, devices and residual lesions according to the French PNDS

Most operated patients are asymptomatic and take no medication; medical treatment is transient in the postoperative period or directed at complications [11]. The French PNDS is the only source in this article with paediatric dosing for these situations, summarised in Table 9; the doses are those of the protocol, published in 2008, and later guidelines do not update them for tetralogy.

Table 9. Medical treatment after surgery and antithrombotic treatment according to the French PNDS

The reactive polycythaemia of residual cyanosis improves oxygen transport and only becomes harmful when excessive [11]. With a haematocrit above 65%, the PNDS requires dehydration to be excluded first (inappropriate diuretic, sunburn, fever, renal or digestive losses, diabetes, insufficient intake) and rehydration; it considers repeated venesections to keep the haematocrit below 65% disappointing, because they stimulate erythropoiesis and induce iron deficiency, which is itself a thromboembolic risk factor; and it notes that some teams use, after specialist advice, myelosuppressive treatment with hydroxycarbamide or pipobroman, with monitoring of platelets, leucocytes and bleeding time, reserving venesection (large-volume with isovolaemic replacement, or small-volume without replacement) for symptoms of hyperviscosity or for an uncontrolled haematocrit [11]. ESC 2020 diverges in management: therapeutic venesection is only indicated with moderate to severe symptoms of hyperviscosity and a haematocrit at least above 65%, without dehydration or iron deficiency, with isovolaemic replacement of 750 to 1000 mL of isotonic saline for each 400 to 500 mL of blood removed; routine venesections should be avoided, iron deficiency (mean corpuscular volume <80 fL, low stores) is treated with supplementation monitored for the rebound effect, and the guideline does not include myelosuppressive treatment [17]. In embolic stroke, the PNDS allows an antiplatelet agent with caution, and in Eisenmenger syndrome in NYHA class III it refers to pulmonary arterial hypertension treatments, namely bosentan and sildenafil [11].

Regarding implantable devices, the PNDS indicates a pacemaker for postoperative high-grade atrioventricular block persisting for more than 7 days, or for intra-Hisian or infra-Hisian block on electrophysiological study, which should be discussed when postoperative complete block has lasted more than 48 hours and high-grade conduction disturbances persist; the epicardial or endocardial route is chosen according to weight, anatomy and local practice, avoiding the endocardial route below 10 kg to preserve venous capital [11]. Later, a pacemaker is indicated for symptoms (presyncope, syncope) caused by sequelar paroxysmal conduction disturbances and is discussed in high-grade intra-Hisian or infra-Hisian block. The implantable cardioverter-defibrillator always requires prior haemodynamic and anatomical assessment at the centre; the PNDS takes up the indications with demonstrated benefit in the general population (cardiac arrest due to ventricular tachycardia or fibrillation without an acute or reversible cause, symptomatic sustained ventricular tachycardia with heart disease, poorly tolerated sustained ventricular tachycardia without a medical or ablative alternative, unexplained syncope with inducible ventricular tachycardia or fibrillation) and recalls that, in children and adolescents, frequent complications require the indication to be reconsidered; ventricular arrhythmias are treated with antiarrhythmics or ablation, and the defibrillator is discussed after failure of these techniques in severe ventricular dysfunction without a surgical solution [11]. Stratification by scores and classes of recommendation in the 2025 American and 2020 European guidelines (Table 8) is later and more detailed [16, 17].

Late atrial tachycardias, usually flutter due to re-entry around scars, require transthoracic or transoesophageal echocardiography before cardioversion, to exclude thrombus; urgent cardioversion is preferably performed by rapid endocardial or transoesophageal atrial pacing, external electrical shock also being effective, under effective anticoagulation with heparin; intravenous class IC and III antiarrhythmics in children are reserved for the centre, because of the risk of sudden death or severe bradycardia at the end of the tachycardia; prevention of recurrences relies on antiarrhythmics and ablation by cryoablation or radiofrequency [11].

For residual lesions, the PNDS sets some thresholds [11]. Residual outflow obstruction is repaired when the RV systolic pressure approaches systemic pressure; in pulmonary atresia and absent pulmonary valve, conduit obstruction is treated by surgical replacement, dilatation or a percutaneous endoprosthesis, valved or not. Pulmonary branch stenoses are treated percutaneously when the gradient at catheterisation exceeds 20 mmHg, with a cutting balloon if necessary; an endoprosthesis is possible in adult-sized patients, for a poor result or from the outset, and little recommended below 20 kg, for lack of long-term studies. A residual VSD is closed, surgically or percutaneously, with a significant shunt (Qp/Qs >1.5), reintervention for another reason or endocarditis, a criterion different from that of ESC 2020, which is based on LV volume overload (Table 8) [17]. Pulmonary valve implantation (homograft, heterograft or percutaneous or hybrid valved stent) is decided by symptoms and functional class, RV volumes on MRI and their evolution, regurgitant fraction, sustained atrial or ventricular arrhythmias and severe tricuspid regurgitation with RV dilatation, without the volumetric thresholds of the American and European guidelines (Table 8); surgery may combine plasty of the pulmonary branches, tricuspid annuloplasty, closure of a residual VSD and arrhythmia surgery. Replacement or repair of the aortic root or aortic valve is rarely needed, biventricular resynchronisation should be performed by experienced teams, heart transplantation is discussed in end-stage failure despite treatment or in refractory ventricular arrhythmias, and heart–lung transplantation in Eisenmenger syndrome [11].

7.7. Infection prevention, anaesthesia, sport and therapeutic education

The indications for curative antibiotic therapy in the child with complex heart disease are those of any child, but a fever lasting more than 8 days requires consultation at the reference or competence centre [11]. In endocarditis prevention, the 2008 PNDS, based on the 2002 French recommendations, considers all complex congenital heart defects, operated or not, as high risk and recommends prophylaxis at all ages, not only for dental procedures with gingival or periapical manipulation or perforation of the oral mucosa, but also for biopsies or incisions of the respiratory mucosa (not for bronchoscopy without biopsy), skin or musculoskeletal procedures, vaginal delivery or caesarean section, endocardial pacemaker implantation and digestive and urinary procedures; the patient should carry the Fédération Française de Cardiologie prophylaxis card, avoid piercings and tattoos and maintain oral and skin hygiene [11]. The ESC restricts prophylaxis to high-risk patients — prosthetic valves, including transcatheter ones, valve repair with a prosthetic ring, previous endocarditis, unrepaired cyanotic heart disease and heart disease repaired with prosthetic material up to 6 months after the procedure, or lifelong if a residual shunt or valvular regurgitation persists — and to at-risk dental procedures; in high-risk non-dental procedures, systemic prophylaxis may be considered (class IIb), and the 2023 guideline no longer recommends clindamycin because of the risk of Clostridioides difficile infection [17, 74]. In practice, an adult with repaired tetralogy without recent prosthetic material, without residual shunt or valvular regurgitation associated with prosthetic material, is not high risk for the ESC, contrary to what the PNDS establishes, whereas the patient with a valved RV–pulmonary artery conduit, a pulmonary bioprosthesis or a transcatheter valve, such as the Melody, is high risk for both [11, 17, 74]. Table 10 compares the dosing.

Table 10. Antibiotic prophylaxis of endocarditis: 2008 French PNDS and ESC 2023

Sources: [11, 20, 74].

For prevention of respiratory syncytial virus bronchiolitis, the PNDS reproduces the 2004 Société Française de Cardiologie criteria for palivizumab, decided after the opinion of the paediatric cardiologist following the child: children under 1 year with haemodynamically significant heart disease that is unoperated, palliated or partially repaired, including tetralogy with frank cyanosis (transcutaneous saturation below 80% at rest); children at high respiratory risk (poorly tolerated heart disease below 6 months at the start of the season, poorly tolerated heart failure despite treatment, respiratory distress, failure to thrive, significant pulmonary hypertension, frank hypoxaemia); children under 1 year who may be admitted during the epidemic season for surgery or catheterisation; and some children over 1 year with poorly tolerated complex heart disease; children operated on or treated by catheterisation with a good result are excluded [11]. These criteria predate nirsevimab. In the EU, palivizumab (Synagis®) is given to children under 2 years with haemodynamically significant heart disease, at 15 mg/kg intramuscularly once a month during the risk season, with no maximum dose defined in the SmPC, with a further dose as soon as the child is stable after cardiopulmonary bypass [75]; nirsevimab (Beyfortus®) is given as a single intramuscular dose of 50 mg below 5 kg and 100 mg from 5 kg in the first season, and 200 mg (2 × 100 mg) in the second season in children up to 24 months who remain vulnerable, with an additional dose after surgery with cardiopulmonary bypass (weight-based dose or 200 mg if within 90 days of the first, 50 mg or 100 mg if later) [76]. Clesrovimab (Enflonsia®), as a fixed single intramuscular dose of 105 mg, was approved by the FDA on 9 June 2025 and authorised in the EU on 15 April 2026, for the first season only, with an additional 105 mg after cardiac surgery with cardiopulmonary bypass in the European SmPC [77, 78]. The choice of antibody and the definition of haemodynamically significant heart disease follow national recommendations. Influenza and pneumococcal vaccines are advised by the PNDS in unrepaired heart disease, according to the national vaccination schedule, and ESC 2020 includes them among the risk-reduction measures for the cyanotic patient [11, 17].

In non-cardiac surgery, the PNDS requires collaboration between the congenital heart disease cardiologist, surgeon and anaesthetist, prior knowledge of the haemodynamic, rhythm and anatomical status (echocardiogram, catheterisation, Holter, haematocrit, renal function) and, in higher-risk patients (pulmonary hypertension, cyanotic heart disease, ventricular failure, shunt), coordination with the centre [11]. In unrepaired tetralogy or with a systemic-to-pulmonary shunt, a fall in systemic resistance should be avoided; spinal and epidural anaesthesia cause arterial vasodilatation and may worsen the right-to-left shunt and reduce shunt flow; hyperventilation during general anaesthesia partly lowers pulmonary resistance; control of the haematocrit and prevention of dehydration reduce the risk of perioperative thrombosis in polycythaemia; in Eisenmenger syndrome, the risk is high, locoregional anaesthesia has proved low-risk and laparoscopy is contraindicated [11]. ESC 2020 agrees that non-cardiac procedures in cyanotic patients or those with complex physiology should be performed at a specialist centre [17].

The PNDS recommends adapted physical activity and advises against overprotection [11]. In operated tetralogy there is no contraindication to sport if right-sided pressure is normal or near-normal, RV volume overload is absent or mild, there is no significant residual shunt and no atrial or ventricular arrhythmia on Holter or exercise testing, and LV function is normal; in the presence of significant pulmonary regurgitation with RV volume overload, RV pressure equal to or above systemic pressure or arrhythmia, only moderate practice of sports of low dynamic and static intensity is allowed (Mitchell class IA, such as billiards, bowling, golf, curling or shooting), with monitoring by echocardiography, Holter and exercise testing; in untreated cyanotic heart disease, only class IA competition; under VKA, sports with a risk of trauma (combat, collision) are contraindicated [11]. Exercise testing for sports fitness should, whenever possible, include ventilatory parameters [11].

Therapeutic education begins at the first contact with the family and is reinforced at each consultation, especially after an intervention: understanding of the heart defect, plan of interventions and consultations, warning signs, management of treatment and drug risks, the hypercyanotic spell and its management, endocarditis prevention, anticoagulation and implantable devices; in adolescence, a dedicated consultation addresses pregnancy risk, contraception and endocarditis prevention, and prepares the transition to the adult clinic [11]. At school, the PNDS recommends informing the management, teachers and school and maternal and child health doctors and drawing up an individualised reception plan; it also recommends anticipating and adapting vocational training and informing the occupational physician when there is a physical limitation [11]. Under VKA, education includes the INR target, stability of a diet rich in vitamin K, interactions, signs of overdose and underdose, urgent management of bleeding and a monitoring booklet; capillary INR self-testing and, subsequently, self-adjustment of the dose may be offered when the patient or a carer is capable, within an educational programme with quality control, and the self-testing device in children on long-term VKA received a favourable opinion from the French committee for the evaluation of products and services on 18 April 2007, with reimbursement conditional on therapeutic education by the centre [11].

7.8. Percutaneous pulmonary valves and regulatory status

Transcatheter pulmonary valve implantation (TPVI) became a surgical alternative first in dysfunctional conduits, then selected native outflows, with comparable results when feasible [17]. Complications include stent fracture, conduit rupture and coronary compression (<2%), warranting balloon testing, and endocarditis incidence 2%–3% annually [17]. Surgical bioprostheses last on average 10–20 years and may subsequently undergo percutaneous valve-in-valve treatment [17].

Table 11. Regulatory status in the United States and the European Union

Medical devices are not authorised by EMA; EU market access depends on CE marking under medical device regulation, not verified through official EUDAMED here.

7.9. Pivotal device trials and limits of interpretation

Table 12. Prospective trials of transcatheter pulmonary valves

These manufacturer-sponsored single-arm studies differ in populations (conduits or native outflows, ages) and composite definitions and cannot compare devices or surgery. None measured mortality or sudden death reduction, and guidelines note replacement has limited ventricular tachycardia and sudden death impact without proven survival benefit [16, 17].

7.10. Developments in the last 12 months and ongoing research

Between October 2025 and October 2026, ACC/AHA/HRS/ISACHD/SCAI adult congenital heart guidance was published (February 2026, corrected April 2026), replacing 2018 [16], alongside ESC cardiovascular disease and pregnancy guidance (2025), stratifying maternal risk by mWHO 2.0 [20]; the next ESC adult congenital guideline is planned for 2028 [89]. Device developments include peer-reviewed 5-year COMPASSION S3 and 3-year ALTERRA results [87, 88] and FDA January 2026 approval of a new SAPIEN 3 pulmonary delivery system (P200015/S068) [83]. Genetic research includes TOF+ exome [13], ciliary variant burden [31], non-coding TBX1 enhancer variants [38] and genetic-diagnosis-associated morbidity/mortality in symptomatic newborns [48, 71].

ClinicalTrials.gov (accessed 7/10/2026) lists, among others, Harmony postapproval (NCT05077774, 174 participants), COMPASSION S3 (NCT02744677, recruiting), PULSTA preapproval (NCT03983512), a phase 4 sodium–glucose cotransporter 2 inhibitor trial in repaired adults (NCT06668389, 106 participants, recruiting) and a free-pulmonary-regurgitation replacement-timing study (NCT04084132), marked recruiting without updates since 2019 [90]. Sodium–glucose cotransporter 2 inhibitors have no approved tetralogy indication and no trial results are published. The search identified no gene-targeted therapeutic trials, which does not prove absence outside that registry.

8. Reproductive Options and Family Counselling

8.1. Empirical risks in isolated tetralogy

When no genetic cause is identified, counselling uses empirical risks, which presuppose prior exclusion of syndromes and Mendelian forms [7, 17]. If there is a Mendelian pattern in the family, these risks no longer apply and counselling follows the observed inheritance [39]. Table 13 compares the values from the sources consulted.

Table 13. Recurrence risks for isolated tetralogy of Fallot

Digilio and colleagues concluded excluding 22q11 deletion requires no change to isolated tetralogy empirical counselling [3]. Values differ by era, method and syndromic exclusion; sources agree risk is greater with affected mothers [12, 17, 39]. Danish data showed same-group recurrence far likelier than a different defect (risk ratio 8.15 versus 2.68), and first-degree familial heart disease explained only 2.2% of population cases [30]. European consensus adds absent family history does not exclude recurrence and miscarriages and variable expression can mean true monogenic risk reaches 50% [12]. Smith notes multifactorial risk rises two- to threefold with two affected children and affected offspring risk is comparable to sibling risk [32]. Oxford also reports more miscarriages with affected mothers (20% versus 10% affected fathers) and monozygotic twin relative risk 15.17 in Denmark [39].

8.2. Risks with an identified genetic cause

In 22q11.2 deletion, about 85% (Oxford) or more than 90% (GeneReviews, A–D deletion) of deletions are de novo; the risk to the offspring of a carrier is 50%, and with parents without the deletion the risk to siblings is low (about 1% according to Oxford), parental germline mosaicism having been described [45, 46]. The French PNDS gives similar values — 80% to 90% de novo deletions and 10% to 20% carrier parents —, systematically proposes testing for the deletion in the parents of any affected child and prenatal diagnosis on amniocytes in a subsequent pregnancy when a parent is a carrier or when a suggestive cardiac malformation appears, and stresses that clinical variability makes counselling difficult [11]. In the presence of any syndrome with a known genetic anomaly, the same protocol tests for it in the parents to define the recurrence risk [11]. The 2025 ESC guideline on pregnancy emphasises this 50% risk to the offspring of women with tetralogy and 22q11.2 deletion [20]. In Alagille syndrome, about 60% of variants are de novo, the risk to the offspring is 50% and expressivity is so variable that prenatal testing does not predict severity [47]. For NOTCH1, FLT4 and JAG1 in the isolated form, transmission is autosomal dominant with incomplete penetrance: there are de novo variants and variants inherited from unaffected parents, affected siblings from an unaffected carrier mother and expression as other heart defects (truncus arteriosus in the daughter of a patient with an FLT4 variant) [5, 8, 27]. The risk of transmitting the variant is 50%, but the risk of tetralogy or another heart defect in carrier offspring is not quantified in the sources consulted.

8.3. Prenatal diagnosis and reproductive options

Fetal echocardiography allows diagnosis of most complex heart defects; the Oxford Desk Reference suggests examinations at 14, 19 and 22 weeks [39], and the ESC recommends fetal echocardiography between 19 and 22 weeks in couples with an affected member, possible from 15–16 weeks [17]; the French PNDS advises it from 18 weeks of gestation, performed by a trained operator, in subsequent pregnancies of a couple with an affected child, and at 18 weeks in women with congenital heart disease [11]. A normal fetal echocardiogram does not exclude a genetic syndrome, as GeneReviews points out for Alagille syndrome [47]. When the familial variant is known, prenatal testing and preimplantation genetic diagnosis are possible; the latter requires a clear genetic diagnosis in the family [7, 47]. In the isolated form without an identified variant, reproductive options rest on fetal echocardiographic surveillance.

8.4. Pregnancy in women with tetralogy

ESC 2025 assigns repaired tetralogy without significant haemodynamic or arrhythmic residual lesions mWHO 2.0 class II (small maternal mortality increase or moderate morbidity increase; local-hospital follow-up and delivery) [20]. Risk is low without residual lesions, rising to 7%–10% arrhythmia and heart failure with regurgitation, impaired RV function or severe obstruction; fetal/obstetric complications reach 15% (mainly prematurity and low weight) and fetal mortality 0.7%; echocardiography is recommended in the first trimester and at 28–32 weeks, more often by functional status [20]. Cardiovascular genetics should precede pregnancy at a specialist centre [20]. ESC 2020 recommends 22q11 deletion testing before pregnancy in pulmonary atresia with VSD because it is frequent [17], and Oxford recommends ensuring adult congenital clinic follow-up and pregnancy-health-impact assessment beforehand [39].

The French PNDS, which predates the mWHO 2.0 classification, does not contraindicate pregnancy in well-repaired tetralogy, pulmonary atresia with ventricular septal defect or absent pulmonary valve, and identifies as residual lesions with a risk of cardiac events raised RV pressure, RV dysfunction secondary to significant pulmonary regurgitation, significant aortic regurgitation and pulmonary hypertension; pregnancy without repair or with residual lesions carries a high risk of complications and of maternal and fetal death, higher still with saturation below 85%, because the fall in peripheral resistance in pregnancy and hypotension during labour increase the right-to-left shunt [11]. In the PNDS risk table, operated tetralogy carries low risk with few or no residual lesions and intermediate to high risk with significant pulmonary stenosis, severe pulmonary regurgitation with or without tricuspid regurgitation or RV dysfunction, lesions to be treated before pregnancy, with heart failure and arrhythmia as complications and Holter in surveillance; in cyanotic heart disease, the risk is intermediate with saturation above 85% and high below 85%, with maternal mortality of 2%, 50% miscarriages, 30% to 50% preterm deliveries and growth restriction, with monitoring of haematocrit, haemoglobin, platelets and saturation, heparin postpartum and oxygen if necessary [11]. The protocol contraindicates pregnancy in NYHA class III or IV, in pulmonary arterial hypertension (mortality of 30% to 50%), in severe LV obstruction, in symptomatic dysfunction of the systemic ventricle or with an ejection fraction below 40% and in dilatation of the ascending aorta above 45 mm, which expressly includes tetralogy and pulmonary atresia with ventricular septal defect among the causes [11].

The PNDS preconception assessment includes information on maternal and fetal risks and on recurrence, echocardiography, exercise testing and Holter, review of drugs with fetal risk (angiotensin-converting enzyme inhibitors, amiodarone) and detection of the obstetric risk of prematurity and growth restriction, and the protocol encourages pregnancies early in life [11]. During pregnancy, it provides for echocardiography in the third trimester (Holter if necessary) and fetal echocardiography at 18 weeks, with precautions in tocolysis with beta-mimetics or calcium channel blockers (hypotension), in corticosteroid therapy for lung maturation (volume expansion), with oxytocics and prostaglandins (bradycardia, hypertension, ischaemia, vasospasm) and with epidural analgesia, whose haemodynamic risk is weighed against that of pain; breastfeeding is not contraindicated if the maternal treatment is not harmful to the child, and most antiarrhythmics and external electrical cardioversion are well tolerated, with a risk of fetal hypothyroidism and neurological injury with amiodarone [11]. The vaginal route is favoured, and caesarean section is reserved for connective tissue disease with an aorta above 40 mm, severe left heart obstruction, prematurity under VKA and recent heart failure [11]. Compared with ESC 2025, the PNDS does not stratify by mWHO 2.0 and schedules echocardiography in the third trimester, whereas the European guideline recommends it in the first trimester and at 28–32 weeks [11, 20]. The indications for caesarean section have also changed: ESC 2025 prefers it with an obstetric indication, VKA use in the 2 weeks before delivery, high-risk aortopathy (mWHO 2.0 class III), hypertrophic cardiomyopathy with severe LV outflow obstruction or refractory acute heart failure, allows it in aortopathy with a maximum diameter above 45 mm or previous dissection and recommends the vaginal route below 40 mm; the 40 mm threshold of the PNDS is therefore a French position from 2008, and the reference is the European guideline [11, 20].

In women with a mechanical valve prosthesis, rare in tetralogy, the PNDS describes a risk of VKA embryopathy of about 5% between 6 and 9 weeks and of cerebral fetopathy of 1% to 2% thereafter, with better maternal safety than heparins; the choice in the first trimester is shared with the patient; VKAs are advised in the second and third trimesters up to 36 weeks, with the same INR target, then switching to heparin; unfractionated heparin is monitored with an activated partial thromboplastin time between 2 and 3 times control or anti-Xa activity of 0.35 to 0.70 IU/mL, and low-molecular-weight heparins with anti-Xa activity of 0.7 to 1.2 IU/mL; prenatal diagnosis is adapted to the period of VKA exposure [11]. Current management of anticoagulation in pregnancy with a mechanical valve is addressed by the 2025 European guideline, which is the reference when it differs from this 2008 protocol [20]. Three PNDS values have been superseded: the risk of embryopathy in the first trimester is given by ESC 2025 as 0.6% to 12%, dose-dependent, and 0.45% to 0.9% with low doses (warfarin ≤5 mg/day, acenocoumarol ≤2 mg/day), with 0.7% to 2% fetopathy thereafter; the target for low-molecular-weight heparins is a peak anti-Xa, 4 to 6 h after injection, individualised by valve type and position between 1.0 and 1.2 U/mL in the guideline text (0.8 to 1.2 U/mL in its dosing table, starting at 125 IU/kg twice daily of enoxaparin or dalteparin and then 100 IU/kg twice daily adjusted to anti-Xa), measured at least weekly until the target and then every 2 to 4 weeks, and not 0.7 to 1.2 IU/mL; and intravenous unfractionated heparin is adjusted to an activated partial thromboplastin time at least 2 times control, reserved for the first trimester and delivery when anti-Xa monitoring is unavailable [20].

For contraception, the 2008 PNDS and ESC 2025 agree on avoiding combined oestrogen–progestogen contraceptives in cyanosis and high thromboembolic risk, but diverge on the copper intrauterine device, which the PNDS contraindicates because of the risk of endocarditis and which the European guideline lists without specific cardiovascular risk (Table 14) [11, 20]. Female sterilisation has been legal in France since 2001 in a consenting adult, with four months of reflection after the first consultation, and ESC 2020 asks that it only be considered after careful discussion of the prognosis [11, 17].

Table 14. Contraception in women with tetralogy: 2008 French PNDS and ESC 2025

Sources: PNDS contraception table by thromboembolic risk and table 8 of ESC 2025 [11, 20].

8.5. Counselling relatives

Determining genetic pattern identifies relatives appropriate for testing or screening [12]. Parental testing is recommended in 22q11.2 deletion because parental diagnosis often follows the child's [7, 45]. When a variant in NOTCH1, FLT4 or JAG1 has been identified, cascade studies identify carriers for whom cardiac assessment is reasonable because of incomplete penetrance; segregation in small families is research evidence rather than proof of pathogenicity [5, 27]. Without an isolated-form variant, Oxford recommends careful parental cardiovascular examination and ECG/echocardiography with historical or examination abnormalities [39]. Pre- and post-test counselling should address secondary findings and direct childhood benefit [7].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

The sources place the birth prevalence of tetralogy at about 3 per 10,000 live births and its share at 5%–10% of congenital heart disease [2, 6]; Page and colleagues use 1 in 3000 births [5], and the Brazilian text on genetic syndromes gives 3–5 per 10,000 births and 7%–10% of heart defects, without sex predominance [14]. Orphanet records the birth prevalence values in Table 15.

Table 15. Birth prevalence of tetralogy of Fallot in Orphanet (validated values)

Source: Orphadata, epidemiology file downloaded on 7/10/2026 [1]. Differences between European registries (from 11.4 per 100,000 in Croatia to 48.2 in Malta) may reflect differences in case ascertainment, inclusion of terminations of pregnancy and period, and should not be read as differences in biological risk without analysis of these sources [1]. No Brazil-specific tetralogy prevalence data were found in the sources consulted. For France, the 2008 PNDS gives an incidence of 0.4 to 0.8 per 1000 births (40 to 80 per 100,000), about 10% of heart defects presenting in the neonatal period, and a prevalence of adults with tetralogy of about 45 per 100,000, without stating the origin of the figures; the incidence range is much higher than the French EUROCAT value recorded by Orphanet (13.8 per 100,000 in 2011), a difference that may reflect the source, the case definition and the inclusion of terminations of pregnancy and that should not be read as temporal variation [1, 11].

9.2. Cause distribution and population data

In the Atlanta population (USA), 22q11.2 deletion had a prevalence of 1 in 5950 births, between 1 in 6000 and 1 in 6500 in White, Black and Asian individuals and 1 in 3800 in Hispanic individuals, and accounted for 1 in every 8 cases of tetralogy [10]. In Sweden, the annual incidence of the deletion was 14.1 per 100,000 live births [46]. Gene studies of the non-syndromic form have been carried out mainly in European populations (829-proband cohort from the United Kingdom, continental Europe and Australia; Canadian cohort of adults of European ancestry by design) [5, 8], and the most recent data on ciliary variants and the TBX1 enhancer come from Han Chinese patients [31, 38]. The NKX2-5 variant NM_004387.4 p.(Phe145Leu) (published protein designation), present in 1 in every 7100 Icelanders, is associated with dilated cardiomyopathy, atrioventricular block, sudden death and ASD, and not with tetralogy [4]. VSD morphology also varies between populations: the doubly committed defect is more frequent in patients from the Far East and Central and South America [2]. The sources do not describe a founder effect for isolated tetralogy.

9.3. Special populations

Adults constitute a growing patient population, with an unrecognised 22q11.2 deletion in more than half of affected cases in a Dutch registry [28]. Premature and low-weight symptomatic newborns have higher postintervention mortality [71]. Women of reproductive age require a preconception assessment (section 8.4). Adults with tetralogy and 22q11.2 deletion have fivefold death risk (HR 5.00) compared with other tetralogy patients (section 11) [29].

9.4. Reference networks and patient associations

ERN GUARD-Heart has a childhood/adult congenital thematic area [21], and ERN ITHACA covers rare malformation syndromes and neurodevelopmental disorders relevant to TOF+ [22]. European Congenital Heart Disease Organisation brings together parent and adult associations [23]. Oxford lists Children's Heart Federation in the UK [39, 91] and Max Appeal for 22q11.2 [45, 92]. In the USA, Adult Congenital Heart Association supplies an adult clinic directory and patient resources [24], and Mended Hearts runs Mended Little Hearts for affected children's families [93].

In France, the PNDS was drawn up by the reference centre for complex congenital heart malformations (M3C), coordinated at the Hôpital Necker-Enfants Malades (Paris), with the Centre Chirurgical Marie-Lannelongue and the adult congenital heart disease unit of the Hôpital Européen Georges-Pompidou, and lists centres with experience in complex heart disease in Lille, Caen, Rouen, Amiens, Rennes, Nantes, Bordeaux, Toulouse, Clermont-Ferrand, Lyon, Grenoble, Marseille, Montpellier, Nancy and the overseas territories (Réunion-Mayotte and Antilles-Guyane) [11]. The reference and competence centres for complex congenital heart disease are now grouped in the CARDIOGEN rare disease health filière, which also brings together cardiomyopathies and inherited rhythm disorders [25]. Diagnosis, initial assessment and follow-up take place at these centres or at facilities linked to them, by a team that includes paediatric and adult congenital cardiology, congenital heart surgery and intensive care, obstetrics, neonatology, genetics, cardiac imaging, rhythmology, psychology and, in syndromic forms, early medico-social action centres, with the general practitioner coordinating local care; tetralogy and the variants covered by the protocol are followed under the long-term condition scheme (ALD no. 5, severe congenital heart disease), whose care protocol is established with the health insurance medical adviser [11]. Two patient associations (AFDOC and ANCC) were part of the PNDS working group, which asks the centres to inform patients and professionals about the associations, through institutional websites, Orphanet and the Integrascol school integration portal [11].

10. Illustrative Clinical Case

10.1. Fetal tetralogy with an FGD5 variant inherited from an unaffected mother (Liu et al., 2025)

A non-consanguineous Chinese couple without other children was referred at 26+3 weeks for complex heart disease in a male fetus [94]. At 12+2 weeks, the crown–rump length and nuchal translucency were normal; at 22+5 another hospital described double-outlet RV, VSD, suspected pulmonary stenosis and microcephaly (head circumference below −2 SD) [94]. Dedicated echocardiography at the authors' centre at 26+3 showed aortoseptal discontinuity with 0.60 cm defect, overriding aorta 0.49 cm diameter, stenotic pulmonary arteries (left 0.15 cm, right 0.22 cm), systolic right-to-left VSD shunt and absent ductus, ultimately diagnosed as tetralogy; growth restriction was present (head circumference −3.47 and estimated weight −2.84 SD) without other structural anomalies [94]. Figure 1 shows echocardiograms (https://pmc.ncbi.nlm.nih.gov/articles/PMC12588575/figure/F1/) [94].

The pregnancy was terminated and fetal exome sequencing, with Sanger confirmation in the parents, identified a heterozygous missense variant in FGD5, NM_152536.4:c.3233C>A p.(Thr1078Lys), also present in the mother, without a cardiac phenotype; the pedigree and chromatograms are in Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12588575/figure/F2/) and the structural model in the Dbl homology domain in Figure 3 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12588575/figure/F3/) [94]. The variant was absent from gnomAD and 1000 Genomes, with mostly deleterious in silico predictions and conservation of the residue; the authors classified it as likely pathogenic using the PS2, PM2 and PP3 criteria and interpreted the absence of a maternal phenotype as incomplete penetrance [94]. FGD5 had been associated with tetralogy in 2019 by the Canadian cohort, in which a truncating variant was found in an adult with tetralogy [8].

Critical appraisal. The case illustrates isolated tetralogy genetics difficulties. First, PS2 (confirmed de novo) conflicts with reported maternal transmission; without it, PM2 and PP3 do not support likely pathogenic classification under ACMG/AMP and the variant should be uncertain. Second, the article uses two transcripts (NM_152536.4 and NM_001320276.2) for c.3233C>A, requiring MANE normalisation before clinical use. Third, FGD5 is a VEGF candidate without NOTCH1 or FLT4 validation. Fourth, fetal growth restriction and microcephaly suggest TOF+ and other causes. Reported actions (termination and future prenatal diagnosis recommendation based on this variant) should not be models: uncertain-variant-based prenatal or preimplantation diagnosis is not recommended by sources requiring a clear familial genetic diagnosis [7].

10.2. Adult tetralogy with a truncating FLT4 variant transmitted to a daughter (Reuter et al., 2019)

In Toronto, a 79-year-old man (TOF158) with tetralogy, right arch, ablated paroxysmal atrial flutter and mild aortic dilatation carried NM_182925.4(FLT4):c.3574C>T, p.(Gln1192*), absent from ExAC and gnomAD; his daughter with tetralogy inherited it [8]. In the current MANE Select transcript, the description is NM_182925.5:c.3574C>T, p.(Gln1192Ter), at NC_000005.10:g.180611443G>A, VariantValidator-confirmed [35]. Nobody in this cohort had documented lymphoedema [8]. This shows vertical transmission with a concordant loss-of-function FLT4 phenotype, advanced age attainable after repair and adult atrial arrhythmia burden; the same study also describes a woman with an in-frame variant of FLT4 whose daughter had truncus arteriosus, illustrating discordant expression [8].

11. Prognosis and Long-Term Follow-Up

11.1. Survival and morbidity

Survival data depend on the surgical era and the population studied (Table 16). Bailliard and Anderson report long-term survival of 85% in patients born 30 years before their review [2], and Page and colleagues report that 85% to 90% of patients survive at least to 30 years [5]. The standardised mortality rate of patients with repaired tetralogy is almost double that of patients with simple defects (ASD and VSD) [17].

Table 16. Long-term cohorts in tetralogy of Fallot

The 94.5% survival at 25 years describes patients who survived repair and does not represent survival from birth; Rotterdam's 25% event-free survival at 40 years contrasts with low late mortality because many required reoperation or developed arrhythmias [18, 19]. Rotterdam subjective health matched Dutch population and exercise capacity was stable despite declining biventricular systolic function [19].

11.2. Arrhythmias and sudden death

Tetralogy particularly associates with sustained monomorphic ventricular tachycardia and sudden death, with a classical rate of 1.5 sudden deaths per 1000 patient-years, low childhood risk accelerating in the third and fourth decades and lifetime sustained ventricular tachycardia risk above 10% [16]. ESC reports sudden death frequency 1%–3.5% retrospectively, with QRS ≥180 ms, LV systolic/diastolic dysfunction and inducible ventricular tachycardia as factors [17]. Atrial fibrillation is associated with lower survival [16]. Risk scores (PREVENTION-ACHD, Brompton, PACES) have been developed, some incorporating CMR late enhancement [16]. In tetralogy adults with 22q11.2 deletion, sudden death proportion was higher (38.5% versus 11.9% of deaths) [29].

11.3. Recommended follow-up

Table 17. Follow-up intervals for the adult with repaired tetralogy (ACC/AHA 2025, adapted from Stout et al. 2018)

Source: [16]. The ACC/AHA guideline also recommends cardiopulmonary exercise testing to complement risk stratification because adults may not recognise declining exercise capacity, and catheterisation when pulmonary pressure and resistance require measurement [16]. The ESC adds Holter monitoring, event recorders and electrophysiological studies in selected patients, identifying unresolved questions about optimal replacement timing in asymptomatic patients with significant regurgitation, transcatheter valve durability and primary-prevention ICD selection [17]. Follow-up should be lifelong and provided by cardiologists trained in congenital heart disease [2].

The French PNDS, which covers children and adults, organises follow-up differently (Table 18) [11]. Specialist follow-up is close in the first year of life and in the year following surgery or interventional catheterisation; after repair, it becomes as a rule annual from the end of the first postoperative year, and is adapted to complications and their treatment; every consultation includes a full clinical examination, 12-lead ECG and Doppler echocardiography [11]. The clinical examination looks for symptoms at rest and on exertion (NYHA class, palpitations, chest pain, presyncope or syncope), fever and signs of endocarditis, change in the murmur, signs of heart failure, arrhythmias and thromboembolic events, and records blood pressure, peripheral pulses and saturation by pulse oximetry; the ECG looks for rhythm and conduction disturbances and assesses RV hypertrophy; the echocardiogram quantifies pulmonary stenoses and regurgitation, tricuspid regurgitation, residual VSDs, aortic regurgitation and aortic root diameter, size and function of both ventricles and pulmonary pressure [11]. Comparison with the 2025 ACC/AHA guideline (Table 17) shows three divergences: the PNDS sets an annual consultation with ECG and echocardiography for the repaired patient, whereas the American guideline allows intervals of 12 to 24 months in stages A and B; the PNDS reserves MRI for severe pulmonary regurgitation on echocardiography, whereas the American guideline provides for periodic CMR every 3 to 5 years even with normal function; and the PNDS considers exercise testing rarely useful in routine follow-up, whereas the American guideline recommends it as an adjunct to risk stratification [11, 16].

Table 18. Surveillance according to the 2008 French PNDS, with comparison with the 2025 ACC/AHA guideline

11.4. Genetic follow-up

At transition to adult care, the European consensus recommends reconsidering unrecognised genetic conditions, documenting three-generation history and consanguinity and offering genetic testing to untested adolescents with section 4's warning signs [12]. Deletion 22q11.2 testing should be offered to never-tested patients because diagnosis changes prognosis (higher adult mortality), extracardiac surveillance and reproductive counselling [28, 29]. NKX2-5 diagnosis requires lifelong conduction surveillance, while GATA6 or GATA4 requires metabolic monitoring [4]. In undiagnosed isolated disease, exome reanalysis may help as new genes emerge [12].

12. Summary and Final Considerations

Tetralogy of Fallot results from anterocephalad outlet septal deviation with VSD, right outflow obstruction, aortic override and RV hypertrophy, affecting approximately 3 in 10,000 live births, with Orphanet birth values of 29.3 per 100,000 in Europe, 23.7 in Portugal and 47.0 in the USA [1, 2]. Approximately 20% are syndromic, principally 22q11.2 deletion (approximately 1 in 8 tetralogy patients), and 80% non-syndromic [6, 10]. Isolated disease has multifactorial architecture including incompletely penetrant rare variants: NOTCH1 and FLT4 contribute most in exome cohorts (almost 7% together), the VEGF pathway (FLT4, KDR) associates with absent pulmonary valve and right arch, and classical transcription factors (NKX2-5, GATA4, GATA6, TBX1) and JAG1 explain a small fraction [5, 8, 27].

All tetralogy patients should undergo CMA for 22q11.2 deletion and other CNVs, including never-tested adults [7, 28]. Extracardiac malformations or neurodevelopmental disorders justify exome sequencing after normal CMA, with approximately one-quarter yield [13]; sporadic isolated yield is low, with broad testing more relevant given family history or specific-gene-suggestive phenotypes. Uncertain and candidate-gene variants should not underpin reproductive decisions.

Surgery enables 94.5% survival at 25 years after repair, but regurgitation, ventricular dysfunction, arrhythmias and sudden death require lifelong CMR, ECG and risk stratification; American 2025 and European 2020 guidance differ on pulmonary replacement volumetric criteria, and percutaneous implantation has extended options to native outflows [16–18]. Genetic diagnoses are associated with greater neonatal morbidity and, for 22q11.2 deletion, fivefold adult death risk [29, 48].

In counselling for the isolated form, the empirical recurrence risks are around 2.5%–3% for siblings and 1.5% to 2.5% for offspring, higher when the mother is affected; with an identified genetic cause, the transmission risk is 50% for dominant forms, but incomplete penetrance and variable expressivity prevent prediction of severity [7, 17, 47]. A woman with repaired tetralogy without residual lesions is at mWHO 2.0 class II risk in pregnancy and should have preconception genetic and cardiological assessment [20]. The ERN GUARD-Heart and ERN ITHACA networks and patient associations complement follow-up [21–23]. The 2008 French PNDS adds paediatric dosing for the hypercyanotic spell, the postoperative period and prostaglandin, with a starting dose of alprostadil lower than that of the label and a unit error for noradrenaline, and retains criteria for endocarditis prophylaxis, genetic testing and contraception that are older than those of the European and American guidelines, which prevail where they diverge [11, 20, 74].

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