Bicuspid Aortic Valve and Associated Aortopathy

A common congenital valvulo-aortopathy with high heritability and heterogeneous genetic architecture (rare Mendelian forms on a polygenic background), carrying a lifetime risk of valvular dysfunction, thoracic aortic dilatation, infective endocarditis and aortic dissection; the unicuspid aortic valve is included as a related entity.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview

The normal aortic valve has three cusps, named by their relationship to the coronary arteries: the right coronary cusp, the left coronary cusp and the non-coronary cusp [7]. The observation of valves with only two unequal leaflets goes back to Leonardo da Vinci, some five hundred years ago; the OMIM (Online Mendelian Inheritance in Man) entry, citing McKusick (1958), credits him with recognising the mechanical superiority of the tricuspid valve over bicuspid and quadricuspid valves [3, 7]. The modern pathological anatomy of BAV was consolidated by Roberts's series of 85 autopsies (1970), which discussed the distinction between congenital and acquired cusp fusion, and by the frequency of 0.9% of isolated BAV in 1,440 autopsies, together with the observation that, with the decline of rheumatic fever, BAV had become the substrate of more than half of isolated aortic stenoses [1, 3].

The link between the valve and the aortic wall was recognised progressively. McKusick (1972) noted the association of BAV with Erdheim cystic medial necrosis; Pachulski (1991) and Hahn (1992) showed by echocardiography that the aorta of patients with a normally functioning or minimally stenotic BAV is larger than that of age- and sex-matched controls, independently of haemodynamics, leading to the interpretation that BAV and root dilatation reflect a common developmental defect [3]. In an autopsy series of 186 patients with aortic dissection studied by Roberts and Roberts over 30 years, 14 (7.5%) had BAV and 2 (1.1%) a unicuspid valve; among the 16 patients with a congenitally malformed valve, 13 (81%) were men, age at death ranged from 17 to 82 years and the entry tear was located in the ascending aorta in all [3].

1.2. From familial aggregation to molecular genetics

The familial nature was documented before the molecular era: Emanuel and colleagues (1978) found a minimum familial occurrence of 17.1% (34.1% including doubtful cases) in the families of 41 patients with surgically confirmed isolated BAV, and Glick and Roberts (1994) described six families with 17 affected individuals [3]. Cripe and colleagues (2004) studied 309 probands and relatives from 50 families by echocardiography and estimated a heritability of 89% for BAV and of 75% for BAV and/or other cardiovascular malformations [19]. In 2005, Garg and colleagues identified heterozygous loss-of-function NOTCH1 variants in two non-syndromic families with autosomal dominant inheritance of BAV and early valve calcification, the first gene associated with human BAV [37]. SMAD6 (Tan 2012), MAT2A (Guo 2015, in families with thoracic aneurysm and BAV), ROBO4 (Gould 2019) and ADAMTS19 followed, the latter in autosomal recessive progressive valve disease (Wünnemann 2020) [16, 38–40]. In 2014, Stittrich and colleagues described heterozygous NOTCH1 variants in five unrelated probands with Adams-Oliver syndrome, four of them with cardiac and vascular defects, and proposed that the scalp and limb defects result from a vasculopathy [6]; in 2024–2025, ClinGen grouped Adams-Oliver syndrome, congenital heart disease, aortic valve disease including BAV and thoracic aneurysm into a single entity, the NOTCH1-related Adams-Oliver spectrum, with definitive validity [17]. Genome-wide association studies (GWAS) successively identified loci near GATA4 (Yang 2017), PALMD, TEX41 and MUC4 (Gehlen 2023) and, in 2026, 36 loci in a meta-analysis of 9,631 cases, which quantified a substantial polygenic contribution [10, 41, 42].

1.3. Nomenclature and reclassification

The Sievers and Schmidtke classification (2007), based on 304 surgical specimens, orders valves by the number of raphes (type 0 without a raphe, type 1 with one raphe, type 2 with two raphes) and by the position of the fused cusps; for more than a decade it was the most widely used [1, 7]. The proportions associated with it (one raphe in 88%, right-left fusion in 71% and right-non-coronary fusion in 14%) describe that surgical series and not the general population [7]; the ESC 2014 aortic diseases guideline indicated, on another basis, fusion of the left and right coronary cusps in more than 70%, of the right and non-coronary cusps in 10–20% and of the left and non-coronary cusps in 5–10% [24]. The international nomenclature and classification consensus published in 2021 simultaneously in the European Journal of Cardio-Thoracic Surgery, the Annals of Thoracic Surgery, the Journal of Thoracic and Cardiovascular Surgery and Radiology: Cardiothoracic Imaging, and endorsed by the Heart Valve Society, the European Association of Cardiovascular Imaging (EACVI), the Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the cardiovascular MRI and CT societies and the international BAV consortium (BAVCon), replaced this classification with a descriptive imaging-based nomenclature, because the Sievers classification does not distinguish fused BAV without a raphe from 2-sinus BAV, does not recognise partial fusion, does not assess the valve symmetry required for repair, does not describe aortic phenotypes and includes in type 2 a valve that is in fact unicuspid [1]. ESC 2024 adopted this nomenclature [5].

1.4. Definitions of the entities covered

Congenital BAV is defined by the demonstration, in a short-axis view of the base of the heart (TTE, transoesophageal echocardiography or TOE, gated CT or MRI), of only two commissures delimiting two functional cusps [1]. Three types are distinguished: fused BAV, in which two of the three cusps are joined within three distinguishable sinuses, with a raphe in about 70% of cases; 2-sinus BAV, with two cusps of similar size and shape, each occupying 180° of the annulus, without a raphe; and partial-fusion BAV (forme fruste), with the appearance of a tricuspid valve but fusion of less than 50% at the base of one commissure («mini-raphe») [1]. Bicuspid aortopathy is dilatation of the thoracic aorta associated with BAV, described in the ascending, root and extended phenotypes [1]. Familial BAV (ORPHA:402075) requires BAV in at least two first-degree relatives [2]. The unicuspid aortic valve, which the consensus excludes from the definition of BAV, is treated as a related entity (section 3.6) [1, 43].

From a nosological standpoint, the consensus groups the BAV condition into three clinical-prognostic subgroups: complex valvulo-aortopathy, in which associated conditions (Turner syndrome, Loeys-Dietz syndrome, Shone complex, severe coarctation) may be more serious than the BAV itself and/or there is early or accelerated valvular dysfunction or aortopathy, diagnosed mainly in children, adolescents and young adults; typical valvulo-aortopathy, the most common group, with progressive valvular dysfunction and/or aortic dilatation without other major conditions, diagnosed in young adults and adults; and undiagnosed or uncomplicated BAV, a lifelong silent condition, defined retrospectively, revealed only at autopsy or by incidental imaging [1]. Life expectancy in the typical form is similar to that of the age- and sex-matched population, and may be reduced in the complex form [1, 26]. Isolated coarctation of the aorta, left-sided heart lesions, the general approach to congenital heart disease, syndromic and non-syndromic heritable aortopathies (Marfan syndrome, Loeys-Dietz syndrome and others) and Turner syndrome enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Valve embryology and the origin of phenotypes

The aortic valve forms from the endocardial cushions of the outflow tract (OFT), in a process that depends on endothelial-to-mesenchymal transition (EMT) of endocardial cells, migration of cardiac neural crest cells and second heart field cells, and subsequent remodelling and excavation of the cushions into thin cusps [1, 7]. BAV results from abnormal fusion of two adjacent cusps or abnormal septation of a primordial cusp [7]. In animal models, the right-non-coronary fusion phenotype is associated with defective EMT during cushion formation, and the right-left fusion phenotype with defective OFT septation due to abnormal neural crest cell activity [7]. The international consensus integrates these data as follows: the three fused phenotypes are explained by abnormal remodelling or excavation of the cushions, or by a mild defect of OFT septation (right-left fusion) or of cushion formation and positioning (right-non-coronary and left-non-coronary fusions); latero-lateral 2-sinus BAV corresponds to a defect of cushion formation and positioning and antero-posterior 2-sinus BAV to a defect of OFT septation, representing a more severe expression of the same mechanism; and partial fusion corresponds to the mildest defect [1]. This gives rise to the concept of a continuous anatomical spectrum of «bicuspidy», from partial fusion to asymmetric fused BAV with a raphe, to symmetric fused BAV and to 2-sinus BAV [1]. The 2025 North American adult congenital heart disease guideline describes most BAVs as isolated abnormal fusion of two adjacent conotruncal endocardial cushions [31]. The shared embryological origin of the aortic valve and the ascending aorta is one of the arguments for the existence of genetic defects common to BAV and thoracic aortic aneurysm (TAA) [7].

2.2. Overall genetic architecture

BAV is sporadic or familial. Heritability was estimated at 89% in a North American cohort of 50 families [19] and at 47% (h² 0.47) in a Spanish cohort of 256 probands and 724 first-degree relatives, in which there was no concordance of valve morphotype between relatives and no significant heritability of aortic dilatation [20]. In rare large families, autosomal dominant inheritance with reduced penetrance and variable expressivity has been observed [7]. Loscalzo and colleagues (2007) prospectively studied 13 families with BAV and thoracic aneurysm: 35% (39/110) of relatives had BAV with aneurysm or isolated aneurysm, two families had unaffected obligate carriers and three had other left ventricular outflow tract anomalies (coarctation, hypoplastic left heart), consistent with reduced penetrance and with the interpretation that BAV and aneurysm are independent manifestations of the same genetic defect [3]. McBride and colleagues (2005), in 124 families of probands with aortic valve stenosis, coarctation or hypoplastic left heart, found left ventricular outflow tract malformations or significant heart disease in 7.7% (32/413) of relatives, a relative risk of 36.9 in first-degree relatives and a heritability of 0.71–0.90, consistent with a complex, probably oligogenic pattern [3, 44]. Family linkage studies pointed to loci on 18q (maximum multipoint lod of 3.8 at 18q22 in an analysis of 353 individuals from 38 families), 5q and 13q, without the responsible genes having been identified [3, 7].

The fraction explained by Mendelian genes is small. According to the international consensus, more than 95% of BAVs are sporadic, without syndromic features and without a variant in known HTAD genes, and each gene accounts for less than 1% of cases [1]; ESC 2024 states that no monogenic model explains the inheritance and that each gene accounts for less than 5% of cases [5]. In a German cohort of 740 patients with non-syndromic, non-familial BAV referred for complications (Bonn, Cologne and Düsseldorf, 2016–2020), compared with 726 population controls, a panel of NOTCH1, SMAD6, ROBO4, GATA4, GATA6 and ADAMTS19 identified 12 rare variants predicted to be deleterious in 15 patients (2%), with no enrichment compared with controls; 10× coverage of SMAD6 was only 77.3%, which may have left carriers undetected [45]. By contrast, the yield is higher in early-onset forms: in 63 probands with BAV complications before the age of 30 years (EBAV cohort, early-onset BAV), exome sequencing identified rare deleterious variants in GATA4, SMAD6 or ROBO4 in 12 (18%), with an enriched burden of SMAD6 and GATA4 in EBAV but not in 487 probands with HTAD (12% of whom had BAV), suggesting that BAV with HTAD is a genetically distinct subgroup [46]. In an exome study of 215 EBAV families, 107 (50%) had variants predicted to be damaging in candidate genes with moderate or strong evidence, including BAV genes (9%) and HTAD genes (19%), research findings of limited individual interpretability [47].

Two complementary hypotheses explain the heterogeneity: oligogenic inheritance, supported by the low penetrance of single-gene mouse models compared with the more consistent penetrance of compound mutants and by the oligogenicity demonstrated in other left ventricular outflow tract malformations, and polygenic architecture, quantified by GWAS (section 2.6) [7, 10]. The male predominance and the frequency of BAV in Turner syndrome further suggest an as yet unidentified X-linked component: among 152 45,X women, 52 (34%) had BAV, and in those who had lost only the short arm of the X (Xp) the frequency was 28.6%, which localises the determinant to Xp [7, 28, 48].

2.3. Genes with Mendelian evidence

2.3.1. NOTCH1

NOTCH1 (9q34.3; OMIM *190198; MANE Select transcript NM_017617.5) encodes a single-pass transmembrane receptor of about 300 kDa, with 36 EGF-like repeats and 3 NOTCH/Lin repeats in the extracellular domain and 6 ankyrin repeats in the intracellular domain; after binding to DLL1, DLL3, DLL4, JAG1 or JAG2 and cleavage by ADAM metalloproteases, the intracellular domain acts as a transcriptional coactivator [7, 49]. In the developing valve, Dll4-Notch1 signalling appears to mediate EMT and Jag1-Notch1 signalling to restrict mesenchymal proliferation after EMT; Notch1-null mice die early with severe heart defects, cardiac-specific loss of Notch1 produces excessive mesenchymal proliferation and valve dysmorphia, and in aortic endothelial cells from human carriers ligand binding does not activate EMT [7]. NOTCH1 suppresses valve calcification by inducing the repressors HEY1/HEY2, which, through BMP2, prevent activation of RUNX2, an osteoblastic transcriptional regulator; loss of this protection is consistent with the early valve calcification of carriers [7, 37]. In the aortic wall, NOTCH1−/− induced pluripotent stem cells (iPSCs) differentiate poorly into mature smooth muscle cells, and Notch1+/− mice on the 129S6 background develop root dilatation without BAV [7]. Patients with BAV have lower tissue and circulating levels of NOTCH pathway components and lower numbers of endothelial progenitor cells than patients with a tricuspid valve, with or without aneurysm [3].

The founding study by Garg and colleagues (2005) described a five-generation European-American family with 11 affected members (six with BAV and seven with calcific aortic stenosis, three of them with a three-leaflet valve; one with mitral stenosis and ventricular septal defect, VSD; two with isolated VSD or tetralogy of Fallot) carrying a nonsense variant described as R1108X, and a Hispanic family with three affected members in two generations carrying a single base-pair deletion; the proband of the latter also had mitral atresia, hypoplastic left ventricle and double-outlet right ventricle [3, 37]. The designation R1108X is the historical notation of OMIM entry 190198.0001 (historical numbering, = NM_017617.5:c.3319C>T p.(Arg1107Ter), ClinVar 12476). Mohamed and colleagues (2006) identified two missense variants, T596M (OMIM 190198.0011; = NM_017617.5:c.1787C>T p.(Thr596Met), ClinVar 264528) and P1797H (OMIM 190198.0012; published designation, with no ClinVar match and with residue 1797 being leucine in the reference protein NP_060087.3, so it was not mapped), in two of 48 sporadic German patients with BAV and thoracic aneurysm, and McBride and colleagues (2008) six missense variants in 91 patients with left-sided heart disease, all also present in an unaffected parent, interpreted as susceptibility alleles insufficient by themselves to disrupt development [3].

Larger series defined the yield. Kerstjens-Frederikse and colleagues (2016), in 428 non-syndromic probands with left-sided congenital heart disease (aortic valve stenosis, BAV, coarctation, hypoplastic left heart), found 14 NOTCH1 variants (3%: 5 splicing, 8 truncating and 1 whole-gene deletion), in 11 of 148 familial probands (7%) and in 3 of 280 sporadic probands (1%); of the 49 additional carriers identified in 14 families, 12 (25%) were asymptomatic, 9 (18%) had right-sided or conotruncal heart disease and 6 of 63 carriers (10%) had thoracic aneurysm; cardiovascular malformation was present in 75% of carriers [50]. Debiec and colleagues (2022) sequenced NOTCH1 in 8 families (36 individuals) and 381 sporadic patients from Leicester (BRAVE study): they found one pathogenic variant, NM_017617.5:c.873C>G p.(Tyr291Ter), in one family and no pathogenic or likely pathogenic (P/LP) variants in sporadic patients; in a review of 64 publications (528 families and 9,449 sporadic patients), the proportion of P/LP variants was 2.1% (95% CI 0.7–3.4%) in non-syndromic families and 0.05–0.08% in sporadic patients, with incomplete penetrance in almost half of the families, leading to the conclusion that NOTCH1 accounts for about 2% of familial BAV and less than 0.1% of sporadic BAV [51]. Clinical Cardiogenetics cites the Kerstjens-Frederikse study for figures of up to 13% of familial cases and 4% of sporadic cases and for reduced penetrance of about 16%, figures that do not appear in the publication (7% of familial probands, 1% of sporadic probands and malformation in 75% of carriers); the original values and those of the Debiec review prevail [7, 50, 51]. NOTCH1 is not a major cause of non-calcified, non-stenotic BAV with high-penetrance aneurysm, but occasionally causes coarctation and hypoplastic left heart syndrome (HLHS), and is more associated with tetralogy of Fallot and HLHS than with isolated BAV [7, 51].

The allelic spectrum of NOTCH1 includes three germline phenotypes: Adams-Oliver syndrome type 5 (OMIM 616028), aortic valve disease/BAV (AOVD1) and a leukoencephalopathy with calcifications caused by de novo gain-of-function variants [6]. In Adams-Oliver syndrome, Stittrich and colleagues (2014) found five heterozygous variants (5' deletion, canonical splicing variant and missense variants at cysteines of the EGF repeats) in unrelated probands, with cardiac and vascular defects in four of the five families, and concluded that NOTCH1 is the most common cause of the syndrome [6]. The leukoencephalopathy was described in 7 unrelated patients with de novo variants (Helman 2022), with increased IP-10 protein in cerebrospinal fluid (a research finding, not a validated test) and calcifying microangiopathy at autopsy; it has no entity of its own in ClinGen or OMIM [6]. The developmental phenotypes result from loss of function (ClinGen haploinsufficiency score 3), and there is no biochemical marker of NOTCH1 deficiency [6]. Somatic variants are tumour drivers (activating in T-cell acute lymphoblastic leukaemia and recurrent in chronic lymphocytic leukaemia, inactivating in head and neck squamous cell carcinoma); no ClinGen, OMIM or GenCC assertion links germline NOTCH1 to cancer predisposition, and the gene is not on the secondary findings lists [6]. In ClinGen, the entity «NOTCH1-related Adams-Oliver spectrum» (MONDO:1060150), autosomal dominant, has since 2024 grouped Adams-Oliver syndrome, congenital heart disease, aortic valve disease including BAV (MIM 109730) and familial thoracic aneurysm and dissection, with definitive validity (7 March 2025): 11 nonsense or frameshift variants in 11 probands from 4 publications, maximum genetic score of 12 points, segregation LOD of 7.12, incomplete penetrance and large intrafamilial variability; the first assessment, from 2016 and restricted to familial thoracic aneurysm, had been limited [17]. The 2023 GeneReviews HTAD panel retains the «limited» association with thoracic aneurysm and dissection [15].

2.3.2. SMAD6

SMAD6 (15q22.31; OMIM *602931) encodes an inhibitory SMAD that competes with SMAD4 for binding to SMAD1 and recruits the ubiquitin ligases SMURF1/2 to degrade BMPR1A and RUNX2, inhibiting bone morphogenetic protein (BMP) signalling; it has an MH1 domain, which binds DNA, and an MH2 domain, which interacts with type I BMP receptors, and is highly expressed in the valves and OFT of the human embryonic heart [6, 7]. In 2012, Tan and colleagues sequenced BMPR1A, BMPR2 and SMAD6 in 90 sporadic cases of cardiovascular malformation and identified the variant p.C484F (MH2 domain), joined by p.P415L and p.A325T in 346 additional cases; p.C484F and p.P415L reduced inhibition of the BMP pathway and p.C484F reduced inhibition of the osteogenic response [38]. Gillis and colleagues (2017) resequenced 22 candidate genes in a strictly defined cohort of 441 patients with BAV and aneurysm (root or ascending aorta ≥4.0 cm in adults or Z ≥3 in children) and 183 controls with a normal echocardiogram: SMAD6 was the strongest susceptibility gene (p=0.002), with causal variants in 2.5% (11 patients: 2 nonsense, 1 in-frame deletion, 2 frameshift and 6 missense in the MH1 and MH2 domains) [52]. Luyckx and colleagues (2019), in 473 non-syndromic patients with thoracic aneurysm (14% with BAV), described 7 new likely pathogenic variants, all in patients with BAV and aneurysm, with reduced penetrance (82%) and variable expressivity in family segregation, and coarctation as a frequent comorbidity [53]. Constitutive loss of Smad6 in the mouse causes embryonic and postnatal lethality with incomplete penetrance, through vascular haemorrhage, and survivors have valve thickening and OFT septation defects [7].

The same heterozygous loss-of-function alleles cause three conditions without genotype-phenotype correlation: cardiovascular malformation (left ventricular outflow tract obstruction and conotruncal lesions, with BAV as the emblematic lesion, aortic dilatation and, at the extreme, HLHS), mainly midline craniosynostosis (metopic and sagittal) and non-syndromic radioulnar synostosis [6]. SMAD6 accounted for 2.3% (18/795) of undiagnosed craniosynostoses and 5.8% of metopic craniosynostoses, with an 18.3-fold enrichment of loss-of-function variants compared with gnomAD, and 7% (13/191) in a midline craniosynostosis cohort, in which penetrance depends on a common risk allele in BMP2 (two-locus inheritance) [6]; in the Luyckx aneurysm cohort, none of the six carriers of a SMAD6 variant and the BMP2 risk allele had craniosynostosis [53]. Therefore, a carrier identified through one of the phenotypes should be assessed for the others, including echocardiography in those identified through craniosynostosis or radioulnar synostosis [6]. ClinGen groups these presentations as «SMAD6-related disease», with definitive validity (15 June 2023), but, unlike SMAD3, SMAD6 has no actionability assertions [6]. Several data are relevant to counselling: in the Calpena series (2020), at least 20 of 26 variants were inherited from an unaffected parent; in craniosynostosis, penetrance is below 60% and depends on a second locus; genotyping of the common polymorphism rs1884302 (BMP2 region), proposed as a modifier, has no clinical utility; functional analysis is important in interpreting missense variants, because the enriched class is loss of function; and splicing variants behave as hypomorphic [6]. Homozygous variants in the MH1 domain, with reduced BMP inhibition and abnormal splicing, were described in 2024 (Luyckx), and SMAD6 also suppresses IL1R-TLR→NF-κB signalling through interaction with PELI1 [6].

2.3.3. ROBO4

ROBO4 (11q24.2; OMIM *607528) encodes a receptor with a function in the endothelium. Gould and colleagues (2019) identified, by exome sequencing in a large family with BAV and thoracic aneurysm, a splicing variant segregating with BAV and/or aneurysm; ROBO4 variants segregated in two families and resequencing of 441 patients showed enrichment of rare variants in probands with BAV and ascending aortic aneurysm compared with controls [7, 39]. Silencing of ROBO4 or expression of the mutant allele in endothelial cells causes impaired barrier function and a synthetic repertoire suggestive of increased EMT, with concordant findings in zebrafish and mouse, pointing to an endothelial aetiology [7, 39]. The corresponding entity is AOVD3 (OMIM 618496), autosomal dominant with incomplete penetrance and male predominance [3, 6]. ClinGen classified the relationship with aortic valve disease 3 (MONDO:0032783) as moderate (24 January 2025; approved by the congenital heart disease expert panel on 9 September 2024): genetic evidence of 4.20 points (2 null variants in 2 probands, 7 other variants in 7 probands and segregation in one family with LOD 2.11) and experimental evidence of 6 points (zebrafish knockout, mouse knockout with normal heterozygotes, mouse knock-in, expression in patient tissue and in the mouse embryo, and biochemical function) [18]. ROBO4 is not in the 2023 GeneReviews gene tables [15].

2.3.4. GATA4, GATA5 and GATA6

The cardiac GATA transcription factors, with zinc finger domains, show pronounced phenotypic variability in humans and mice, suggesting modulation by other genetic and/or environmental determinants [7].

GATA4 (8p23.1; OMIM *600576) has a central role in heart and endocardial cushion formation; Gata4−/− is lethal at the embryonic stage, without a primitive heart tube [7]. Rare variants are associated mainly with atrial septal defect (ASD) and VSD, and ClinGen classifies the relationship with structural congenital heart disease of multiple types as definitive (curation of 5 May 2026); extracardiac phenotypes include neonatal or infantile diabetes (series of 5 patients, 4 with onset in the first week of life) and testicular anomalies, and the 8p23.1 microdeletion (ORPHA:251071), which includes the gene, adds diaphragmatic hernia and developmental disorders [6]. Functional studies show that p.Asn273Lys (second zinc finger) reduces DNA binding and transactivation and that p.Gly221Arg (N-terminal zinc finger) abolishes activation of the anti-Müllerian hormone promoter, synergy with NR5A1 and binding to FOG2, which explains the testicular phenotype; ClinVar lists 141 pathogenic, 18 likely pathogenic and 567 VUS variants (including multigene CNVs), and, unlike NKX2-5, GATA4-related ASD is not associated with conduction disease [6]. In iPSC-derived cardiomyocytes, GATA4 variants from septal defects reduce affinity for the target sequence and interaction with TBX5, and a model with the variant described in the source as c.886G>A p.G296S (not normalised) showed impaired contractility, calcium handling and metabolic activity (preclinical data) [54]. In BAV, the GWAS by Yang and colleagues (2017; 466 cases and 4,660 controls, replication up to 1,326 cases and 8,103 controls) identified a non-coding variant 151 kb from GATA4 and near-significance for the coding variant p.Ser377Gly, and CRISPR disruption of GATA4 in iPSCs impaired EMT [41]. This variant is numbered on NM_002052.5; on the MANE Select transcript NM_001308093.3 it corresponds to c.1132A>G p.(Ser378Gly) (NC_000008.11:g.11757066A>G), a one-codon difference between transcripts [49]. The GATA4 locus was confirmed in the 2023 GWAS (p=1.61×10⁻⁹) [42].

GATA5 (20q13.33; OMIM *611496) is expressed exclusively in endocardial cells and in the cushions of the atrioventricular canal and OFT [7]. Mice with endocardial cell-specific loss of Gata5 develop hypoplastic hearts and right-non-coronary fusion BAV with partial penetrance (about 25%), with reduced Jag1, increased Rbpj-κ and a 20–30% reduction in Notch signalling; Nos3 and Tbx20 have been suggested as targets [7, 55]. In 100 patients with BAV (77% men; aortopathy in 59%), Padang and colleagues (2012) found four rare non-synonymous variants in the transcriptional activation domains (Gln3Arg, Ser19Trp, Tyr142His, Gly166Ser), one per patient, the last in a familial case with aortopathy [56]; Bonachea and colleagues (2014) found p.Gln3Arg and p.Leu233Pro in 2 of 78 patients (2.6%), both with BAV and coarctation, and only p.Gln3Arg reduced transcriptional activity in vitro [55]; Shi and colleagues (2014), the source Orphanet uses for GATA5, identified p.Y16D and p.T252P (source notation, without a c. description) in two families, among 110 patients with BAV, with reduced transcriptional activity [2, 57]. Comparable heterozygous variants have been described in isolated VSD, dilated cardiomyopathy, atrial fibrillation and tetralogy of Fallot (p.R187G and p.H207R in two families with autosomal dominant Fallot), and recessive forms in double-outlet right ventricle (homozygous p.Y142H) and in one case with hydrops, heart disease and clitoromegaly (p.Ser19Trp/p.Arg202Gln in compound heterozygosity) [6, 7]. In ClinVar, NM_080473.5:c.424T>C p.(Tyr142His) and c.56C>G p.(Ser19Trp) have conflicting classifications and c.605G>A p.(Arg202Gln) is of uncertain significance; ClinGen has not curated GATA5, GenCC assigns it limited to moderate evidence, and the corresponding OMIM entity is CHTD5 (617912), with dominant and recessive inheritance [6]. Heterozygous missense variants of GATA5 should therefore be interpreted with caution.

GATA6 (18q11.2; OMIM 601656) is highly expressed in the embryonic heart and pancreas; de novo variants cause pancreatic agenesis with congenital heart disease (ASD, VSD, tetralogy of Fallot, patent ductus arteriosus, double-outlet right ventricle), and ClinGen classifies GATA6-related congenital heart disease, with or without pancreatic agenesis or neonatal diabetes, as definitive, with heart disease in 83% of probands in the largest cohort [6, 7]. Gata6+/− mice have high-penetrance right-left fusion BAV, through a mechanism of second heart field cells (Isl1+), neither endothelial nor neural crest, with dysregulation of MMP9 and abnormal valve remodelling [7, 58]. Human evidence is limited: a parent of a patient with GATA6-related ASD had BAV, a single rare variant (p.E386, source notation, without a c. description and with no ClinVar record located) was reported by Xu and colleagues (2018) among 152 patients with BAV, and common variants with nominal significance did not survive correction for multiple testing [7, 58]. The extracardiac phenotype has consequences for follow-up: in the Exeter cohort, GATA6 accounted for 24 of 795 (3%) cases of neonatal diabetes, and the GeneReviews on neonatal diabetes attributes about 5% of the permanent form to it (different denominators); four heterozygous parents had diabetes diagnosed between 12 and 46 years of age, a mosaic carrier had heart disease without diabetes, and gallbladder agenesis and diaphragmatic hernia have been described; therefore, a carrier identified through heart disease needs lifelong monitoring of glycaemia and exocrine pancreatic function [6].

2.3.5. MAT2A

MAT2A (2p11.2; OMIM *601468) encodes methionine adenosyltransferase 2A. Guo and colleagues (2015) identified, in a large family with autosomal dominant thoracic aneurysm variably associated with BAV, the variant NM_005911.6:c.1031A>C p.(Glu344Ala), and in another proband c.1067G>A p.(Arg356His), at residues conserved down to zebrafish; mat2aa knockdown disrupted cardiovascular development and the mutant mRNA rescued the phenotype less well [16, 49]. Carriers have a predisposition to thoracic aneurysm and dissection and more frequent BAV [29]. The ClinGen curation for familial thoracic aneurysm and dissection is limited (5 December 2025), as in the GeneReviews panel, whose table attributes the MAT2A row (non-syndromic HTAD and BAV) in error to Pannu 2007, an article on MYH11; the primary source is Guo 2015 [6, 15, 16]. Orphanet links MAT2A to the familial thoracic aneurysm and dissection entity (ORPHA:91387) as a candidate gene [13].

2.3.6. ADAMTS19 and other genes

ADAMTS19 causes non-syndromic progressive valve disease with autosomal recessive inheritance: two consanguineous families with four affected members had homozygous truncating variants, and the knockout mouse develops aortic valve dysfunction, with a Wnt–LEF1–Adamts19–Klf2 axis in valve interstitial cells [40]. ClinGen classified the relationship with recessive congenital heart disease as limited (8 July 2024), and no biallelic variants were found in the German sporadic BAV cohort [6, 45].

NKX2-5 is located at 5q35.1, a cytoband confirmed in NCBI Gene, Orphanet and GeneGuidance (the 5q34 location given in Clinical Cardiogenetics is outdated) [2, 6, 7]. Nkx2.5+/− mice have BAV in 11%, and of the more than 50 human variants described in ASD, VSD, HLHS and tetralogy of Fallot only two have been associated with BAV: p.Arg25Cys (NM_004387.4:c.73C>T, conflicting classifications in ClinVar), in a patient with Down syndrome, membranous septal aneurysm, coarctation and BAV, and p.Lys192* (source notation, with no ClinVar record located), identified by Qu and colleagues (2014) among 142 patients with BAV, absent in 400 controls, segregating in a three-generation autosomal dominant family with BAV and almost abolishing transcriptional activity and synergistic activation with GATA5; this is the source Orphanet uses for NKX2-5 [2, 6, 7, 59]. ClinGen classifies NKX2-5-related congenital heart, conduction and myopathic disease as definitive (7 November 2024), with haploinsufficiency 3 (a 5q35 deletion that includes the gene is causal), but the gene is not unequivocally recognised as a BAV gene [6, 7]. The conduction phenotype has implications for the interpretation of an NKX2-5 variant found in a patient with BAV: atrioventricular block is progressive and postnatal (Schott 1998) and was the primary manifestation in almost a quarter of those affected in one series (Benson 1999); in a review of 59 variants in 202 patients, 74% had ASD and conduction disturbance and 19 of 120 (15%) patients with familial ASD and conduction disturbance died suddenly (Ellesøe 2016); and in Iceland the variant p.Phe145Leu, present in 1 in 7,100 inhabitants, is associated with dilated cardiomyopathy, sudden death, high-grade block and ASD (Sveinbjornsson 2018); the same gene causes congenital non-goitrous hypothyroidism type 5, usually mild, and warrants serial ECGs and assessment of relatives [6]. TBX20, with definitive validity for autosomal dominant congenital heart disease (7 July 2026), has variants linked to valve and septal defects [6, 7].

Other genes have an unestablished association. A de novo translocation disrupting the 5'UTR region of AHDC1 and the 3'UTR of MATR3 was described in an individual with BAV, coarctation, patent ductus arteriosus and global developmental delay (the latter probably explained by AHDC1), and 15% of heterozygous mice with truncated Matr3 have BAV [7]. In the EBAV cohort, rare COL1A1 (n=5) and COL1A2 (n=5) variants were identified in 10 of 215 families (4%), a 30-fold enrichment compared with European populations; only two were glycine substitutions in the triple-helical domain, and the probands had AR and/or aneurysm requiring repair and subtle features (joint hypermobility, recurrent fractures, dental changes), without a severe osteogenesis imperfecta phenotype [9]. In the same cohort, rare 22q11.2 CNVs were found in 20 of 272 probands (7.4%) versus 3.6% in controls (prevalence ratio 2.1; 95% CI 1.3–3.2), segregating with BAV in families; carriers had more psychiatric diagnoses and learning difficulties but not the typical 22q11.2 deletion syndrome phenotype, and CNVs including TBX1 were enriched [8].

2.3.7. BAV in heritable aortopathies

BAV is more prevalent in several forms of HTAD. ACC/AHA 2022 reports BAV in about 10% of patients with Loeys-Dietz syndrome (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3) and increased prevalence in HTAD due to NOTCH1, ACTA2, MAT2A, SMAD6 and LOX [21]; the international consensus indicates 4–15% in HTAD due to TGF-β pathway genes and ACTA2, versus 1% in the general population, with rapidly progressive root dilatation [1]; AATS 2018 indicates 2.5–17% in Loeys-Dietz syndrome and 3% in familial aneurysm due to ACTA2 [28]; and Clinical Cardiogenetics reports an incidence five times higher than in the general population in Loeys-Dietz syndrome [7]. In a Montalcino Aortic Consortium registry of 816 carriers of pathogenic HTAD variants (preprint not peer reviewed), 48 (6%) had BAV, with enrichment in TGFBR1/TGFBR2 carriers (10% versus 5%; prevalence ratio 1.93; 95% CI 1.08–3.43); BAV was associated with AR (37% versus 11%), an earlier first aortic event (24 versus 40 years) and more proximal aortic repair (56% versus 30%), but not with more dissection (13% versus 18%) [60]. Screening of TGFBR1/TGFBR2 in BAV cohorts found only p.Val387Met (NM_003242.6:c.1159G>A, conflicting classifications in ClinVar), of uncertain significance, and no variant in 13 families with BAV and aneurysm [3, 7]. Older studies suggested BAV in up to 5% of patients with Marfan syndrome, without confirmation in large observational studies; fibrillin-1 is reduced in the aorta and pulmonary artery of patients with BAV, rare patients with BAV and aneurysm without Marfan syndrome have FBN1 missense variants, and FBN1 polymorphisms are associated with TAA but not with BAV [7]. The combination of an HTAD variant with BAV may explain some cases of the root phenotype, and in such cases the specific gene guides treatment and the timing of intervention [1].

2.4. Gene-by-gene summary and clinical validity

Table sources: [1, 6, 8, 9, 16–18, 39, 40, 45, 50–53, 55, 57, 60].

2.5. Normalised variants

The variants cited were normalised in VariantValidator against the GRCh38 genome and MANE Select transcripts; variants described only by the protein change and without a ClinVar record keep the source notation, because manual conversion is not admissible [49].

2.6. Polygenic architecture and genome-wide association studies

The first BAV GWAS (466 cases and 4,660 controls) located a signal near GATA4 [41]. Gehlen and colleagues (2023), with 2,236 patients and 11,604 controls, identified a new locus at 3q29 (rs2550262, p=3.49×10⁻⁸), in linkage disequilibrium with a missense variant of MUC4 predicted to be deleterious, whose disruption in zebrafish delayed valve development, and confirmed PALMD (p=3.97×10⁻¹⁶), GATA4 and TEX41; they estimated that a substantial fraction of heritability is polygenic and that about 20% of the observed heritability was explained, with fetal endothelial cells as the main transcriptional source [42].

The meta-analysis by Thériault and colleagues (2026) pooled 9,631 cases and 56,046 controls of European ancestry from 17 studies in Europe and North America and identified 36 genome-wide significant loci (p<5×10⁻⁸), 32 of them new; three new loci had been associated with calcific aortic stenosis (ACTR2, TMEM44, LPA) and two with ascending aortic diameter (PRDM6, FGF9) [10]. In replication in FinnGen, All of Us and UK Biobank (4,321 cases and 1,085,665 controls), the 36 loci had the same direction of effect and 30 reached p<0.05; heritability explained by single-nucleotide polymorphisms (SNPs) was 11.7% (standard error 1.4%) on the liability scale, assuming a prevalence of 1% [10]. Integration with expression data (eQTL) from 484 human aortic valves, 326 aortas and 326 left ventricles prioritised KANK2, ERBB4, PRDM6 and STRN, among ten genes with the most evidence, and pointed to the Wnt pathway (LEF1, WNT4); knockdown or knockout of WNT4, LEF1, STRN and KANK2 in zebrafish disrupted heart and OFT valve development (preclinical data) [10]. A polygenic score derived in 8,853 cases and 50,600 controls and tested in 778 cases and 5,446 controls from Quebec was associated with BAV with an odds ratio (OR) of 2.07 (95% CI 1.90–2.25) per standard deviation and of 3.39 (2.83–4.06) above the 90th percentile, with an area under the curve (AUC) of 0.692 (0.673–0.711); in UK Biobank, the score was associated with aortic valve surgery (OR 1.52 per standard deviation), aortic stenosis (1.34), AR (1.19), thoracic aneurysm (1.26) and, marginally, atrial fibrillation or flutter (1.03) [10]. The cohorts were mostly surgical and European, which biases the sample towards complicated BAV, and an AUC of 0.69 does not allow individual clinical use of the score [10].

Bermudez and colleagues (2026) applied a natural language processing algorithm (sensitivity 0.955 and precision 0.984) to echocardiogram reports from the Million Veteran Program and identified 83,704 individuals with definite BAV (2.4% of 3.5 million veterans with analysed reports, a selected and predominantly male population, not a population prevalence) [63]. The multi-population GWAS of 9,571 cases versus 631,091 participants, with individuals genetically similar to European, African, admixed American and East Asian reference populations, identified 7 loci, two known (PALMD, TEX41) and five new (PRDM6, TGFBI, LPA, ADAMTSL1, ATXN2), enriched in pathways of extracellular matrix organisation, O-glycosylation and smooth muscle differentiation [63]. The genetic correlation with aortic stenosis was strong (rg=0.86) and with thoracic aneurysm and dissection moderate (rg=0.45); there was colocalisation with aneurysm at the PRDM6 locus (posterior probability 0.52) and with stenosis at PALMD and LPA (posterior probability 1), and the effect of LPA was age-dependent (OR 1.30–1.31 from 50 to 80 years, 0.90 below 50), suggesting that this locus relates more to stenotic progression, or to misclassification of calcified tricuspid valves with acquired fusion, than to congenital morphology [63]. OMIM records that the intronic LPA variant rs10455872-G is associated with aortic valve calcification (OR per allele 2.05) and with incident aortic stenosis [3]. NOTCH1 and PALMD are also associated with calcific aortic stenosis of tricuspid valves, and BAV is enriched in first-degree relatives of patients with calcific stenosis of a tricuspid valve [10].

2.7. Animal models

Mouse models show partial penetrance and reinforce the oligogenic hypothesis. Nos3−/− mice (endothelial nitric oxide synthase, eNOS, a target of Gata5 and Notch1) have BAV in about 27%, and penetrance rises to about 73% when Notch1+/− is added; Nos3−/−;Notch1+/− adults develop aortic sinus dilatation independent of haemodynamics, and eNOS expression is reduced in aortic endothelial cells of patients with BAV, inversely correlated with aortic diameters, without causal NOS3 variants in humans [7]. Absence of Alk2 (Acvr1) in the cushion mesenchyme causes BAV in about 78%, but human ALK2 gain of function causes fibrodysplasia ossificans progressiva without described BAV; Hoxa1 causes BAV in 25% and Krox20 (Egr2) in 27%, whereas the human recessive HOXA1 phenotypes and the EGR2 phenotypes (peripheral neuropathies) do not include BAV; endocardial loss of Brg1 thickens the valves, with about 35% bicuspid, and human SMARCA4 variants cause Coffin-Siris syndrome or rhabdoid tumour predisposition, without BAV [7]. Robo1;Robo2 compound mutants all have BAV, unlike single mutants, and the Slit2 knockout has BAV with very low penetrance; no human disease is linked to these genes, and the genes of the Notch and Robo-Slit pathways have very similar expression patterns in the developing heart [7]. The models also give clues to the cellular origin: BAV arises when Alk2 (type I activin receptor of the BMP pathway) is deleted in the endocardial cushion mesenchyme, but not in neural crest knockouts, indicating a cell-autonomous origin; Hoxa1 is expressed in cardiac neural crest precursors, upstream of the genes for its specification and maturation; Krox20 is expressed in the primordia of the semilunar and atrioventricular valves and activates Col1a1 and Col3a1, and the 10% penetrance when the deletion is restricted to the neural crest or endothelium suggests compensation by neighbouring cells; and Brg1 is the ATPase subunit of the BAF chromatin remodelling complex, which regulates neural crest proliferation, differentiation and apoptosis and EMT [7]. In three iPSC-derived cardiomyocyte models of HLHS, NOTCH1 variants correlated with defective cardiomyogenesis, and reactivation of NOTCH signalling partially rescued the phenotype in vitro (preclinical data) [54].

2.8. Pathophysiology of aortopathy and valvular dysfunction

For decades, aberrant post-valvular haemodynamics was considered the sole trigger of aneurysm in BAV. Evidence for common genetic defects includes families in which BAV and aneurysm co-occur or manifest separately, aneurysm progression after valve replacement, aortic dilatation in normally functioning BAVs and in newborns, and the shared embryological origin of the valve and the ascending aorta [3, 7, 22]. The current interpretation is mixed: the root phenotype, more frequent in young men with AR and associated with more dissection after isolated valve replacement, may express a genetically determined connective tissue disease, whereas the ascending phenotype appears to be driven mainly by altered flow [1]. Four-dimensional (4D) flow MRI shows that, in right-left fusion, the jet impinges on the outer curvature of the proximal ascending aorta, with greater wall shear stress (WSS) in the root and proximal aorta, and that, in right-non-coronary fusion, the jet is directed posteriorly towards the proximal ascending aorta and the outer wall of the distal ascending aorta, which correlates with the association of this phenotype with dilatation of the ascending aorta and arch; asymmetric dilatation, predominantly of the greater curvature, coincides with the zone of maximum WSS [1]. These associations are not universal, and concomitant stenosis alters the WSS pattern independently of the fusion phenotype [1]. Histologically, the aortic media of patients with BAV and dissection shows severe degeneration of elastic fibres, similar to that of Marfan syndrome [3]. The aortic wall of BAV-associated aneurysms shows increased TGF-β signalling, as in Marfan syndrome, arterial tortuosity syndrome, degenerative aortic disease and, paradoxically, Loeys-Dietz syndrome (caused by receptor loss of function), suggesting common pathogenic mechanisms of the arterial wall [29]. Loscalzo and colleagues (2007) and Rossi's prospective MRI study of stenotic BAV (2013) are among the arguments cited in favour of genetic defects shared between the valve and the aorta [7].

Valvular dysfunction follows another axis: stenosis results from progressive fibrosis and calcification, favoured by the loss of mechanisms that repress osteoblastic differentiation (NOTCH1–HEY–RUNX2 and BMP inhibition by SMAD6) and by factors shared with calcific stenosis of the tricuspid valve (LPA, PALMD), and AR results mainly from prolapse of the conjoint cusp and dilatation of the annulus, sinuses and sinotubular junction [1, 6, 7, 63]. The presence of a raphe is associated with progression of dysfunction, especially stenosis, and with future valve surgery [1, 64].

3. Clinical Spectrum and Manifestations by System

3.1. Valve morphology and frequency of phenotypes

Fused BAV accounts for about 90–95% of cases, 2-sinus BAV for 5–7% and partial-fusion BAV for an unknown proportion [1]. Within the fused type, right-left fusion is the most frequent (70–80%) in American, European and Asian populations, followed by right-non-coronary fusion (20–30%) and left-non-coronary fusion (3–6%); a raphe is present in about 70% of fused valves and may only become visible years after diagnosis [1]. In the Copenhagen Baby Heart Study, the 196 newborns with BAV were distributed across Sievers type 0 (8.7%), type 1 (90.8%: right-left fusion 75.0%, right-non-coronary 13.8%, left-non-coronary 2.0%) and type 2 (0.5%) [22]; in the international registry of 2,118 adults with BAV (1991–2015; 72.0% men), 88.8% had a raphe [64]. Right-non-coronary and left-non-coronary fusion are more prevalent in Asian populations, and in syndromic forms right-non-coronary fusion is more common in Down syndrome, whereas right-left fusion predominates in Turner syndrome and Shone complex [1].

3.2. Valvular dysfunction

The most frequent complication of BAV in adults is valvular dysfunction requiring replacement or repair, determined mainly by stenosis; in the community, the risk of aortic valve replacement (AVR) 25 years after diagnosis exceeds 50% [1]. In a meta-analysis of natural history studies cited by ACC/AHA 2020, 13–30% of patients developed ≥moderate AR and 12–37% ≥moderate AS during follow-up [23]. Significant AR is less common than AS (30% versus 70%) and more frequent in men, whereas women have been described as more susceptible to AS, an association that requires confirmation [1, 7]. In BAV, severe stenosis appears earlier than in the tricuspid valve and often with aortopathy, and the prevalence of BAV rises sharply in younger patients with AS: about half of patients undergoing aortic valve surgery before the age of 70 years have BAV, and up to 20% of patients aged 80 years or more undergoing valve replacement have congenital BAV [1, 7, 30]. Pure AR rarely coexists with normal aortic diameters and is more often associated with dilatation of the ascending aorta and/or root [30]. The ESC 2020 adult congenital heart disease guideline describes BAV as the most common cause of congenital valvular aortic stenosis, with variable progression according to initial severity, calcification, age and atherosclerotic risk factors, and faster when the closure line is more eccentric or antero-posteriorly oriented; in asymptomatic patients with good exercise tolerance, sudden death is rare even in severe stenosis, and after the onset of angina, dyspnoea or syncope the prognosis deteriorates rapidly [4].

Morphology influences progression. In the registry of 2,118 patients, the presence of a raphe was associated with more significant AR (33.1% versus 24.1%) and AS (38.7% versus 21.5%), more valve replacement at 5 years (24.4% versus 18.0%) and higher mortality at 5 years (9.5% versus 4.4%), but the raphe was not an independent predictor in multivariable analysis [64]. Right-non-coronary fusion is associated with a higher prevalence of AS in adults, independently predicts progression of AR, and in children and adolescents is associated with faster progression of stenosis and regurgitation [1]. Mitral valve prolapse affects 2–3% of patients with BAV, a figure similar to that of the general population, but isolated prolapse of the anterior leaflet, including «giant» prolapse, is twice as frequent and may complicate mitral repair [1].

3.3. Bicuspid aortopathy

The prevalence of aortic dilatation in BAV varies with the population and the definition: 20–84% according to ACC/AHA 2022 and the ESC 2020 adult congenital heart disease guideline (which also reports up to 80% over a lifetime), 40–70% according to the international consensus and 20–40% according to ACC/AHA 2020, which describes it as independent of valve function [1, 4, 21, 23]. ESC 2014 defined dilatation as a diameter >40 mm regardless of body surface area (or >27.5 mm/m² in people of short stature) [24]. Dilatation most often affects the tubular ascending aorta, sometimes extending to the arch [21]. The ascending phenotype accounts for about 70% of bicuspid aortopathy (70–75% in ESC 2024), the root phenotype for about 20% (15–20% in ESC 2024; 10–20% in ACC/AHA 2022) and the extended phenotype for 5–10% [1, 5, 21]. The two main phenotypes tend to correspond to two patient profiles: the older patient, of either sex, with valve sclerosis or stenosis and the ascending phenotype, and the younger patient, usually male, with AR and the root phenotype, associations that are not universal [1]. The root phenotype grows faster, is associated with more events after isolated valve replacement, worse survival without surgery and more type A dissection, and may progress to dilatation of the tubular ascending aorta («extended root phenotype»), with progressive effacement of the sinotubular junction as the initial sign; the ascending phenotype may extend to the arch, especially in right-non-coronary fusion [1, 5]. ESC 2014 described a subgroup of less than 15%, almost exclusively young men, with predominant root dilatation without substantial valve disease [24]. Sex differences depend on the indexing method: in the Polish RE-BAV registry (808 adults, 588 men), classified according to the international consensus, women had more of the extended phenotype (34.7% versus 23.3%) and men more of the root phenotype (15.1% versus 7.8%) and moderate to severe AR (50.3% versus 29.1%) [65].

Aortic growth is slow and variable: 0.2–0.9 mm/year in the series cited by Clinical Cardiogenetics, about five times that of the tricuspid valve [7]; 0.5 mm/year on average in the tubular ascending aorta, 0.2–1.2 mm/year in the various series and no further dilatation in half of patients after 3 years, according to ESC 2014 [24]; 0.2–2.3 mm/year, usually 0.4–0.6 mm/year, in the tubular ascending aorta, the site of maximum growth [1]; 0.47 mm/year (0.2–2.3) in a prospective study of 90 adults followed for 4.8 years [21]; and 0.2–0.6 mm/year according to ESC 2024 [5]. ACC/AHA 2022 reports 0.6 mm/year in the root phenotype and 0.3 mm/year in the ascending phenotype, versus 0.1 mm/year in sporadic dilatation with a tricuspid valve and 2.6 mm/year in the root in Marfan syndrome [21]. Age, baseline diameter, family history, type of valvular dysfunction and location of dilatation influence the growth rate, and larger aortas expand faster, according to Laplace's law [1, 7]. In Olmsted County (Minnesota), the incidence of new aneurysm in patients without baseline aneurysm was 84.9 (95% CI 63.3–110.9) per 10,000 patient-years, with a relative risk (RR) of 86.2 compared with the general population, and the incidence of aortic surgery at 25 years was 25% [66]. In a cohort of adults without baseline aneurysm (<4.5 cm), 13% developed aneurysm over 14±6 years and the 25-year risk was 26% [21]. ESC 2014 reported that 27% of adults with BAV without significant valve disease require cardiovascular surgery within 20 years [24]. Aortopathy is already present in the neonatal period: in the Copenhagen cohort, newborns with BAV had a larger root and tubular ascending aorta than the others (differences of 0.43 and 0.46 mm) and 65 of 196 (33.2%) had aortopathy (62 with Z ≥3 and 3 with coarctation) [22].

3.4. Coarctation and associated cardiovascular lesions

Coarctation of the aorta is present in 7–10% of adults with BAV according to the international consensus and in 4–10% according to ACC/AHA 2025, and BAV is present in 50–60% of patients with coarctation (50–75% according to ESC 2014, 50–85% according to ESC 2024 and up to 85% according to the ESC 2020 adult congenital heart disease guideline) [1, 4, 5, 24, 31]. Right-left fusion is strongly associated with coarctation in children, and ESC 2014 described coarctation as associated only with this type of fusion [1, 24]. ESC 2020 describes coarctation as a generalised arteriopathy, with associated lesions beyond BAV (ascending aortic aneurysm, subaortic or supravalvular stenosis, mitral or supramitral stenosis, Shone complex), aberrant right subclavian artery in 4–5% and intracerebral aneurysms in up to 10%, and associated with Turner and Williams-Beuren syndromes [4]. The international consensus and AATS consider coarctation a risk factor for aortic complications, and ACC/AHA 2022 includes it in the list of risk factors for dissection, although in a cohort of 499 patients with BAV (24% with coarctation) there was no difference in adverse aortic events [1, 21, 28]. Coarctation, arch hypoplasia and the genetic approach to left-sided heart lesions follow the general principles of congenital heart disease.

AATS 2018 summarises the frequency of BAV in associated cardiovascular conditions.

Source: AATS 2018, Table 1, modified from Braverman [28].

VSD, ASD and patent ductus arteriosus are also more frequent in patients with BAV and their relatives [7]. In studies of left ventricular non-compaction cardiomyopathy, BAV was found in 3 of 64 patients (5%), in addition to three case reports, a cumulative proportion from heterogeneous studies [67]. Intracranial aneurysms, generally small (<10 mm), have been described in 10% of patients with BAV versus 1% of controls, and in 10% of patients with coarctation [5, 28].

3.5. Infective endocarditis and aortic dissection

Infective endocarditis (native and prosthetic in the aortic position) occurs in about 2% of patients in contemporary cohorts, with a population incidence of about 14 cases per 10,000 patient-years, 11 times higher than in the general population [1]; the ESC 2020 adult congenital heart disease guideline indicates 0.3% per patient-year of follow-up, the same rate as cardiac mortality [4]. In the Olmsted County community cohort with a median follow-up of 19 years, the cumulative lifetime incidence was 6%, higher than that of dissection (1.6%) [26]. In aortic endocarditis, perivalvular complications and abscesses may be more frequent in BAV than in the tricuspid valve [68].

Dissection is the most feared and least frequent complication. In Olmsted County, among 416 patients followed for 16±7 years, there were 2 dissections, an incidence of 3.1 (95% CI 0.5–9.5) per 10,000 patient-years and an age-adjusted relative risk of 8.4 (2.1–33.5) compared with the general population; the incidence rose to 17.4 per 10,000 patient-years in patients aged ≥50 years at entry and to 44.9 in those with baseline aneurysm, and fell to 1.5 when estimated including undiagnosed BAVs [66]. The ESC 2020 adult congenital heart disease guideline summarises the incidence of dissection as 8 times higher than in the general population but low in absolute numbers (31 per 100,000 patient-years, that is, 3.1 per 10,000), much lower than in Marfan syndrome and other HTAD, and higher when coarctation is present [4]. In a 2025 meta-analysis of unrepaired BAV (20 studies, 5,819 patients with reconstructed curves), dissection occurred at 0.06 per 100 patient-years (95% CI 0.01–0.12) [27]. The international consensus indicates a risk of about 0.5% in patients with a diameter ≥45 mm, generally below 1% [1]; in a systematic review of 13 studies with more than 11,000 patients, dissection occurred in 0.4%, and in a series of 918 patients with serial imaging in less than 0.1% [23]. AATS estimates that up to 5% of patients with BAV will have a dissection during their lifetime, which, given the prevalence of BAV (1 in 50–100 people), makes it a relevant cause of dissection, although recent studies show lower rates, especially in young people [28]. In clinical and autopsy series of aortic dissection, BAV is present in 4–9% of cases (2–9% of type A and 3% of type B dissections according to ESC 2014), and Clinical Cardiogenetics reports 9–28% of dissections before the age of 40 years without identifying the source series [7, 24]. In an era before preventive surgery, type A dissection occurred in 6% of untreated patients with BAV and dilatation over 65 months [24]. Dissection may occur without prior dilatation, as in all thoracic aortic diseases, and is classified by the Stanford and DeBakey criteria [15]. Dissection is extremely rare in young children and rare in adults without aortic dilatation [1]. After isolated valve replacement, dissection at 15 years was 0.55% in BAV, 0.41% in the tricuspid valve and 5.5% in Marfan syndrome (Itagaki study) [28].

3.6. Unicuspid aortic valve

The unicuspid aortic valve is a congenital anomaly distinct from BAV in the international consensus, which excludes it from the definition of BAV and notes that Sievers type 2 (two raphes) corresponds in fact to an incompletely defined unicuspid valve [1]. Its prevalence, age at presentation, prognosis and associated conditions are not equivalent to those of BAV, and the genetic and embryological origins of unicuspid, bicuspid and quadricuspid valves may not be closely linked [1]. In the Copenhagen Baby Heart Study, only 1 of the 196 newborns with an abnormal valve (0.5%) had type 2 morphology [22], and in the Roberts and Roberts autopsy series of aortic dissection, 2 of 186 patients (1.1%) had a unicuspid valve [3]. In the North American GenTAC registry, 17 patients with a unicuspid valve compared with 17 matched patients with BAV had similar baseline characteristics and aortic dimensions, but more frequent and more severe stenosis (higher gradients and smaller valve area); the authors interpreted the unicuspid valve as the extreme of the bicuspid spectrum and considered it reasonable to apply BAV surveillance and intervention recommendations to it [43]. The small size of this series limits the conclusions, and the sources consulted do not describe genes specific to the unicuspid valve. The quadricuspid valve is also excluded from the definition of BAV [1].

3.7. Natural history by cohort

Natural history studies include patients under surveillance and operated on when indicated; survival figures therefore describe the course of BAV under the usual care of the period, not untreated natural history.

Sources: [21, 26–28, 66, 69, 70].

In patients with BAV and minimal valvular dysfunction, mortality is similar to that of the general population, and survival of individuals without significant valvular complications approaches that of individuals with a tricuspid valve [7, 69]. ACC/AHA 2022 adds that, after isolated valve replacement, the risk of aortic events is low in stenosis with mild to moderate dilatation and higher in regurgitation with the root phenotype: in 56 patients operated on for regurgitation with a root of 4.0–5.0 cm, 34% had adverse aortic events [21].

3.8. Presentation by age

In the fetus and newborn, BAV is usually silent; the Copenhagen cohort showed AR in 14.7% of newborns with BAV versus 1.3% of the others and aortopathy already present in one third [22]. In children and adolescents, complex forms (coarctation, Shone complex, Turner syndrome, Loeys-Dietz syndrome) and congenital stenosis predominate, and right-non-coronary fusion progresses faster [1, 26]. In young adults and adults, typical valvulo-aortopathy appears, with progressive dilatation, AR (especially in young men with the root phenotype) and stenosis appearing earlier than in the tricuspid valve; in older people, BAV manifests mainly as calcific stenosis, and distinguishing it from a calcified tricuspid valve with acquired fusion becomes difficult [1, 30]. About one third of patients develop cardiovascular complications from BAV or associated anomalies, and most remain asymptomatic for long periods [7].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

BAV is diagnosed at all ages, in diverse settings and often incidentally, and cannot be reliably diagnosed by auscultation alone or from non-specific complaints such as fatigue, dyspnoea or palpitations [7]. Clinical Cardiogenetics reports a mid-systolic ejection click at the apex in 60–70% of cases, a figure that does not appear in the BAVCon consortium publication it cites [7]; in a series of 35 consecutive patients with Turner syndrome, 12 (34%) had isolated non-stenotic BAV and the presence of a systolic ejection click correlated closely with the echocardiographic finding [3]. Suspicion should arise in several settings: unexplained dilatation of the root or ascending aorta on an echocardiogram, because BAV may be the cause and the valve should be studied in every patient with ascending aortic dilatation [5, 21]; aortic stenosis in a young or middle-aged patient [30]; coarctation of the aorta, Shone complex or supravalvular aortic stenosis [28]; a woman with BAV or aneurysm and short stature or ovarian insufficiency, who should have a karyotype to exclude Turner syndrome [15]; first-degree relatives of patients with BAV, thoracic aneurysm or dissection [5, 21]; parents and siblings of probands with aortic stenosis, coarctation or HLHS, in whom BAV may be asymptomatic [44]; patients with features of Loeys-Dietz, Adams-Oliver, Kabuki or 22q11.2 deletion syndrome (section 6) [7, 21, 71, 72]; patients with midline craniosynostosis or radioulnar synostosis carrying a SMAD6 variant [6]; BAV with ASD and progressive atrioventricular conduction disturbance in the family, suggesting NKX2-5 [6]; endocarditis of a native aortic valve; and aortic dissection in a young adult [7]. On CT coronary angiography acquired only in diastole, partial or complete cusp fusion may go unnoticed and the valve may be taken for tricuspid, so the valve should be assessed in every study and, whenever possible, in systole [1].

4.2. Warning signs in the known patient

Some findings indicate a higher risk of aortic complications and prompt closer surveillance or referral to a multidisciplinary aortic team: rapid aortic growth (≥3 mm/year in the ESC 2024 and ACC/AHA 2022 definitions; >3 mm/year in AATS 2018; >0.5 cm/year in ACC/AHA 2020), maximum diameter ≥50 mm, the root phenotype, severe AR, coarctation, uncontrolled or resistant arterial hypertension, a family history of dissection or unexplained sudden death at a young age, age below 50 years with short stature or a long ascending aorta (≥11 cm), and a desire for pregnancy [1, 5, 21, 23, 28]. In the assessment of athletes, the 2025 AHA/ACC statement indicates a multigenerational family history and genetic evaluation for HTAD when the aortic z-score is ≥3, there is a family history of aortic disease, cerebral or peripheral aneurysm or unexplained sudden death at a young age, or features of connective tissue disease [73]. In non-syndromic HTAD, dilatation usually precedes dissection, but dissection may occur below conventional thresholds, and the onset and rate of progression vary widely within families [29]. Progressive valvular dysfunction identifies the patient who needs regular assessment: in Olmsted County, echocardiographic valve degeneration at diagnosis was associated with more than 70% of events at 20 years and made it possible to separate these patients from low-risk patients, eligible for episodic follow-up [69].

4.3. Emergency situations

Type A aortic dissection (involving the ascending aorta, according to the Stanford classification) is the potentially fatal complication: historical mortality was estimated at 1–2% per hour, with maximum risk in the first 48 hours, and most out-of-hospital deaths result from retrograde rupture into the pericardium with tamponade; the mortality of elective repair in tertiary centres is substantially lower than that of emergency surgery [15]. In the International Registry of Acute Aortic Dissection (IRAD), up to 60% of acute type A dissections occurred at diameters below 5.5 cm, showing that diameter thresholds do not eliminate risk [15]. Infective endocarditis with perivalvular complications and symptomatic severe AS are the other situations requiring immediate assessment in a centre with cardiac surgery; in AS, the onset of angina, dyspnoea or syncope marks rapid deterioration of the prognosis, and the ESC 2020 adult congenital heart disease guideline considers surgery urgent in symptomatic patients [4, 30, 68].

4.4. Newborn and population screening

No newborn or population screening programme for BAV is recommended in the guidelines consulted. The Copenhagen Baby Heart Study, which examined 25,556 newborns by echocardiography in the first 60 days of life, is a population research study and not a screening programme [22]. Guidelines recommend targeted screening of first-degree relatives (sections 8 and 11), and ESC 2024 considers the age at which such screening should begin to be undetermined [5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Morphological criterion and distinction from acquired fusion

The diagnosis of BAV requires demonstration, in a short-axis view of the base of the heart, of only two commissures delimiting two cusps, ideally in systole, because in diastole a BAV may appear tricuspid [1, 28]. In the long axis, systolic doming of the conjoint cusp and an eccentric closure plane suggest BAV, with greater reliability in right-left fusion [1, 7]. The report should describe the type and phenotype of the BAV and valve function, the presence and characteristics of the raphe, the size, shape and symmetry of the cusps, and the presence and phenotype of aortopathy, as well as the presence or absence of coarctation [1]. The symmetry of fused BAV is defined by the angle between the commissures of the non-fused cusp: symmetric at 160–180°, asymmetric below 160° and very asymmetric below 140°, a situation that approaches the tricuspid valve and makes repair more demanding; the angle is measured by TOE before repair [1].

A fibrosed, calcified or rheumatic tricuspid valve may show acquired fusion of two cusps that is difficult to distinguish from congenital BAV [1]. On surgical or pathological inspection, the «pseudocommissure» (insertion of the raphe into the aortic wall) lies lower in the root than the true commissures, the angle between the fused cusps is obtuse in congenital fusion and acute in acquired fusion, and the cleavage plane on the ventricular surface of the fused cusps is absent in congenital fusion and present in acquired fusion; in severe calcific stenosis, information from the surgeon and above all from the pathologist is decisive [1].

5.2. Imaging modalities

TTE is the first-line modality for the diagnosis and phenotyping of BAV, the haemodynamic assessment of valvular dysfunction, the initial measurement of the thoracic aorta, the exclusion of coarctation and other congenital lesions and the assessment of complications such as endocarditis and dissection [1]. TOE helps when TTE does not visualise the valve well, has a sensitivity of up to 92% and specificity of up to 96% for the diagnosis of BAV, is mandatory in the assessment of endocarditis and has excellent accuracy in the diagnosis of dissection, but is invasive and may require sedation; three-dimensional TTE is generally preferred to TOE when greater precision is sought [1, 7]. In moderate to severe stenosis and valve calcification, echocardiographic distinction between a tricuspid valve and BAV has an accuracy of about 70%; cardiac MRI is more sensitive and less specific than echocardiography, with accuracy above 90% [7]. The ESC 2020 adult congenital heart disease guideline considers echocardiography the reference standard for the valve, with occasional TOE for planimetry in non-calcified valves, exercise testing recommended in asymptomatic patients (especially with moderate to severe AS), dobutamine stress echocardiography in low-flow, low-gradient AS, CT for the calcium score in low-gradient AS (bearing in mind that AS in young people is not necessarily calcified) and catheterisation only when non-invasive assessment is inconclusive, for the coronary arteries or for valvuloplasty [4].

ECG-gated CT and MRI are the reference standard for measuring the thoracic aorta, because they measure diameters perpendicular to the longitudinal axis using the double-oblique technique and allow exact comparison of the same anatomical levels [1]. MRI is preferred in younger patients (below 50 years of age) and in those who will undergo repeated examinations, because it does not use ionising radiation, and allows tissue characterisation, quantification of myocardial fibrosis and 4D flow study [1, 28]. CT has superior spatial resolution, should include the systolic phase (retrospective gated acquisition, thin slices below 1 mm, 50–100 mL of contrast at 4–6 mL/s) to assess the valve, identifies raphe calcification by its attenuation pattern (usually above 130 Hounsfield units) and is the reference standard for preoperative and pre-TAVI assessment, also allowing assessment of the coronary arteries [1]. The abdominal and pelvic aorta does not need to be studied in isolated BAV, unless there is a family history of abdominal or iliac aneurysm or suspected coarctation [28].

5.3. Aortic measurement and definition of dilatation

Measurements are reported at the annulus, sinuses of Valsalva, sinotubular junction and mid-ascending aorta (with separate measurement of the root and the tubular ascending aorta), and include the arch and descending aorta whenever possible; Doppler of the proximal descending aorta and abdominal aorta, or comparison of blood pressure in the arms and legs, serve to exclude coarctation [23, 28]. In adults, the echocardiographic convention is end-diastolic leading edge-to-leading edge measurement, generally equivalent to inner edge-to-inner edge measurement by CT or MRI, except at the root, which TTE systematically underestimates in BAV (asymmetric sinuses); a dilated (>45 mm) or asymmetric root should therefore be measured by CT or MRI [1, 15]. In children, z-scores adjusted for body surface area are used, with dilatation defined as Z >+2.0 [1]. In adults with typical valvulo-aortopathy, the international consensus classifies dilatation as mild between the upper limit of normal for age, body size and sex and 45 mm, moderate between 46 mm and 50–54 mm, and severe from 55 mm without risk factors or from 50 mm with risk factors [1]. As patients vary greatly in size, reporting adjusted values is also recommended, such as the ratio of cross-sectional area to height (πr² in cm² divided by height in m), in which values above 10 cm²/m are associated with a worse outcome; ESC 2024 proposes 13 cm²/m for the ascending segment in BAV (approximately 54 mm in men and 53 mm in women, for the average European heights of 1.80 m and 1.67 m) and considers that, at 50 years of age, an ascending aorta of 40 mm is the upper limit of normal for a large body surface area [1, 5]. The difference between examinations is a reliable measure of progression only when both use the same modality, the same anatomical level and the same method, with side-by-side comparison; a discrepancy between TTE and CT/MRI greater than 2 mm (AATS) or of at least 3 mm (ESC) justifies surveillance by CT or MRI [1, 5, 28].

5.4. Diagnostic imaging recommendations

Sources: [4, 5, 21, 23, 28, 31].

Earlier recommendations, now superseded, show the evolution: ESC 2014 recommended initial TTE in all patients (I, C), MRI or CT when TTE does not accurately assess the root and ascending aorta (I, C), serial measurement at an interval according to size, growth and family history (I, C), annual measurement above 45 mm or with growth >3 mm/year (I, C) and confirmation by CT or MRI above 50 mm or with growth >3 mm/year (I, C) [24]; and ACCF/AHA 2010 gave class I (level B) to assessment of the root and ascending aorta in all patients with BAV [34]. COR (North American class of recommendation): 1 recommended, 2a reasonable, 2b may be considered; LOE (level of evidence): B-NR non-randomised data, C-LD limited data, C-EO expert opinion. European classes: I recommended, IIa should be considered, IIb may be considered, III not recommended.

5.5. Functional assessment and biomarkers

Grading of AS uses the general criteria for valvular heart disease: severe high-gradient AS with mean gradient ≥40 mmHg, peak velocity ≥4.0 m/s and valve area ≤1.0 cm² or ≤0.6 cm²/m² [30]. The ESC 2020 adult congenital heart disease guideline uses the following criteria, with normal flow.

Source: ESC 2020, Table 12 [4].

The 2015 AHA/ACC statement for athletes, adapted from ACC/AHA 2014, used similar limits (mild <3 m/s, <20 mmHg and >1.5 cm²; moderate 3–4 m/s, 20–40 mmHg and 1.0–1.5 cm²; severe >4 m/s, >40 mmHg and <1.0 cm²), with exact boundaries that differ from the European ones [74]. The CT valve calcium score (>2,000 Agatston units in men and >1,200 in women, with sensitivity and specificity of about 85%) supports the diagnosis of severe AS in discordant cases, but should be interpreted with caution in BAV, which may have severe AS without marked calcification [30]. Exercise testing with assessment of the blood pressure response is useful in asymptomatic AS and before starting sport, and NT-proBNP is mentioned in the 2025 adult congenital heart disease guideline as a marker of early adverse left ventricular remodelling [30, 31, 75].

5.6. Genetic testing: indications and divergences

ESC 2024 considers that genetic testing is not indicated in isolated BAV and reserves it for patients with syndromic features, a family history of aortic disease or aneurysms and dissections of medium-sized arteries beyond the thoracic aorta, allowing it in the root phenotype [5]. ACC/AHA 2022 recommends medical genetics assessment in BAV with HTAD or with features of Loeys-Dietz syndrome (1, C-LD) and indicates that, when BAV with aneurysm is familial, the patient should be assessed, counselled and tested by a medical geneticist or a specialist in genetic aortopathy, bearing in mind that most patients with BAV and aneurysm who are tested have no pathogenic variant, even in familial forms [21]. The international consensus reserves testing for the minority with suspected HTAD because of syndromic features, early or severe vascular disease or a family history of dissection, a group that includes carriers of TGFBR1 variants without recognisable Loeys-Dietz features but with rapidly progressive root dilatation [1]. The authors of Clinical Cardiogenetics proposed a broader threshold (all probands with BAV and aneurysm before the age of 60 years and all index patients with a family history of BAV, aneurysm or unexplained sudden death), which is broader than that of current guidelines [7]. Recent data suggest also considering testing in BAV with a family history of HTAD, sinus of Valsalva aneurysm or Loeys-Dietz features (preprint data) and CNV analysis in early-onset or complex BAV [8, 60]. The ESC 2020 adult congenital heart disease guideline indicates that rare pathogenic variants explain less than 5% of bicuspid aortic disease, that routine genetic testing is not indicated and that it may be considered in familial cases, based on the 2020 consensus of the ESC working groups and the European Society of Human Genetics (ESHG) on genetic counselling and testing in adult congenital heart disease [4, 76].

For thoracic aortic disease in general, Clinical Cardiogenetics proposes a flowchart adapted from the VASCERN clinical pathway: genetic evaluation and testing are indicated in thoracic aortic dissection, root aneurysm in a child with a z-score ≥3, an adult with a z-score ≥3.5, and an adult with a z-score between 2.5 and 3.5 if aged 60 years or less, or over 60 years without hypertension, with z-scores calculated by formulas adjusted for age and body surface area [29]. The yield of testing in HTAD is 15–30%; in early-onset sporadic thoracic dissection in the GenTAC registry, there were pathogenic variants in 9% and VUS in HTAD genes in up to 28%, data that support testing in dissections before the age of 56 years; panels vary widely between laboratories, larger panels increase the probability of VUS, gene-disease validity should be established (ClinGen tools) and the authors propose a low threshold for testing in HTAD [29]. The method of choice is next-generation sequencing (HTAD panel or exome with an HTAD gene filter), and the clinical assessment of a thoracic aneurysm includes family history, physical examination and ophthalmological assessment to exclude syndromic forms; in ACTA2 carriers, the disease often affects the distal thoracic aorta, which justifies more extensive imaging by CT or MRI [29]. In congenital heart disease with syndromic features, a complex defect or intellectual disability, the Oxford Desk Reference indicates genomic analysis (microarray, panel, exome or genome), a three-generation pedigree covering heart disease and neonatal deaths, cardiovascular examination of both parents (with echocardiography and ECG if there is an abnormality) and DNA storage before cardiac surgery or extracorporeal membrane oxygenation; exomes show an excess of de novo truncating variants in syndromic congenital heart disease [77].

The GeneReviews on HTAD recommends multigene panels with genes of definitive or strong association, possibly extended to genes of moderate or limited evidence, and considers exome or genome sequencing when there is overlap with syndromes in which aortic disease is rare (Noonan syndrome, neurofibromatosis type 1, Alagille syndrome); the genome can detect deep intronic variants, but exome or genome sequencing is unlikely to increase actionable findings in most patients [15]. Findings that increase the probability of a variant are aneurysm or dissection before the age of 60 years, a family history of thoracic aortic disease, unexplained sudden death or aneurysms of other arteries, and features of Marfan, Loeys-Dietz or vascular Ehlers-Danlos syndrome or of smooth muscle dysfunction [15]. A panel restricted to BAV genes has too low a yield to be cost-effective, so these genes are usually included in extended congenital heart disease and/or aortopathy panels [7]. In a woman with BAV and/or aneurysm and features of Turner syndrome (short stature, ovarian insufficiency), a peripheral blood karyotype is indicated, with fluorescence in situ hybridisation (FISH) or study of another tissue when low-level mosaicism is suspected [15].

5.7. Limits of tests and interpretation

A negative result does not exclude a genetic cause: a genetic cause is identified in only 20–30% of individuals with a family history of thoracic aortic disease without syndromic manifestations, and in families with autosomal dominant thoracic aneurysm panels identify a pathogenic variant in about 20–25% [15, 21]. According to GeneReviews, a carrier of a pathogenic variant in an HTAD gene has HTAD by definition and follows the gene-specific management, with imaging of other arteries (aneurysms, moyamoya-like cerebrovascular disease, coronary disease) guided by family history and the molecular cause [15]. Panel sequencing may have incomplete coverage of some genes (in the German cohort, only 77.3% of SMAD6 with 10× coverage), does not reliably detect copy number variants without targeted analysis, nor deep intronic variants outside the captured regions, and testing in leucocytes may not detect somatic mosaicism [8, 15, 45]. Interpretation is difficult because rare variants in the best-established genes (NOTCH1, SMAD6, ROBO4, GATA5) are uncommon, almost never fully penetrant and associated with diverse phenotypes, and because several genes have only limited or moderate validity [6, 7]. The report should state the gene, the transcript with its version (for example NM_017617.5 for NOTCH1), the HGVS nomenclature at DNA and protein level, the zygosity and the classification according to the ACMG/AMP criteria (American College of Medical Genetics and Genomics/Association for Molecular Pathology) [49, 61]. A pathogenic (class 5) or likely pathogenic (class 4) variant allows cascade testing; for a variant of uncertain significance (VUS), cascade testing is not advisable, although segregation analysis may be considered to obtain or refute evidence [7]. The available polygenic score, with an AUC of 0.69, has no individual clinical utility [10].

5.8. Practical algorithm

In the presence of BAV, the first step is a complete TTE with phenotyping of the valve according to the international consensus, grading of dysfunction, measurement of all accessible segments of the thoracic aorta and exclusion of coarctation [1, 21]. If any segment is not visualised, measures ≥45 mm (or >45 mm in ESC 2024), there are discrepancies between serial examinations or coarctation cannot be excluded, gated CT or MRI of the whole thoracic aorta follows, with preference for MRI in patients under 50 years of age [5, 28]. The next step is nosological classification (complex or typical valvulo-aortopathy) and identification of risk factors (root phenotype, severe AR, coarctation, growth ≥3 mm/year, hypertension, family history of dissection or sudden death), which determine the surveillance interval and the surgical threshold (sections 7 and 11) [1, 5]. In parallel, a three-generation pedigree is drawn, syndromic features are sought and echocardiographic screening of first-degree relatives is decided (section 8) and, in the situations referred to in section 5.6, genetic evaluation [5, 15, 21].

5.9. Prenatal and preimplantation diagnosis

BAV is a malformation present in the fetus, and the Copenhagen cohort showed that the associated aortopathy is also already manifest at birth [22]. The sources consulted do not describe the performance of fetal echocardiography in detecting isolated BAV. After the birth of a child with HLHS, the Oxford Desk Reference recommends offering specialist fetal echocardiography in subsequent pregnancies and echocardiography to the parents, and for complex heart disease suggests assessments at 14, 19 and 22 weeks [44, 77]. In HLHS, the same book indicates genomic analysis (microarray, panel or exome/genome) and, when unavailable, karyotype with FISH for 22q11.2, and offers specialist fetal echocardiography in subsequent pregnancies, unless a definitive normal prenatal genetic diagnosis is obtained [44]. Prenatal molecular diagnosis or preimplantation genetic testing are technically possible only when a P/LP variant has been identified in the family, and the incomplete penetrance and variable expressivity of BAV genes limit the predictive value of these results [7, 51]. In HTAD with a known variant, both can be offered in most countries; in a French study of patients with Marfan syndrome, 74% were in favour of prenatal testing, and professionals generally agree that the subject should be handled by a multidisciplinary team [29].

6. Differential Diagnosis

The differential has two levels: the morphological distinction between congenital BAV and other anomalies or acquired changes of the aortic valve, and the identification of syndromes and heritable aortopathies in which BAV is a manifestation, because these modify the surgical threshold, family screening and counselling.

BAV has also been reported incidentally in familial non-compaction myocardium due to an exon 14 MYH7 variant, in a case report of a child with Joubert syndrome, severe AS and ASD, and in the joint dislocation syndrome with congenital heart disease due to B3GAT3, with uncertain membership of the spectrum [7].

6.1. Isolated BAV and heritable aortopathies

The most important differential in an adult with BAV and aortic dilatation is HTAD. In isolated BAV, dilatation usually predominates in the tubular ascending aorta, grows slowly and is associated with valvular dysfunction; predominant root dilatation, especially in a young patient with AR, a family history of dissection or sudden death, aneurysms of other arteries and syndromic features should raise suspicion of HTAD [1, 5, 15]. The ESC 2025 pregnancy guideline points out that the presence of BAV does not exclude non-syndromic HTAD [92]. In the family history of aortopathy it is not enough to ask about aortic disease: intracerebral arterial disease, early coronary disease, congenital heart disease (especially coarctation and ductus arteriosus) and BAV should be included [29]. Up to 20% of patients with aortic aneurysm or dissection have an affected first-degree relative, and the younger the proband the greater the probability of affected relatives [29]. The gene-specific surgical thresholds for HTAD differ from those for BAV.

6.2. BAV and Turner syndrome

In Turner syndrome (about 1 in 2,500 live-born females, with congenital heart disease in about half), BAV is present in 23–50% of patients according to Smith's and in about 30% according to AATS and Clinical Cardiogenetics, with coarctation in 7–18%; BAV has a similar frequency in 45,X patients (34%) and in those who have lost only Xp (28.6%), and up to 12.6% of women with coarctation have Turner syndrome [4, 5, 7, 28, 48, 78]. The incidence of dissection is about 40 per 100,000 person-years, versus 6 per 100,000 in the general population, and ESC 2020 recommends that all patients be seen by a cardiologist at least once [4]. In pregnancy through oocyte donation, a North American survey (146 treated patients, 101 pregnancies) estimated a risk of death from aortic rupture or dissection of about 2%, supported by French data, which justifies echocardiography and cardiology assessment before attempting pregnancy; dissection is more frequent with prior coarctation and hypertension [79]. In these patients, dilatation should be assessed by diameters indexed to body surface area (severe dilatation from 2.5 cm/m² in women over 15 years of age) [1].

6.3. Unicuspid valve and calcified tricuspid valve

The unicuspid valve is distinguished by the presence of a single functional commissure, earlier and more severe stenosis and, in the old classification, by Sievers type 2 (section 3.6) [1, 43]. In older people with calcific stenosis, the distinction between BAV and a tricuspid valve with acquired fusion may be impossible by imaging, and genetic studies of older patients may include calcified valves misclassified as bicuspid [1, 63].

6.4. Syndromic and non-syndromic heritable aortopathies: distinguishing features

The Clinical Cardiogenetics table summarises the HTAD entities with which BAV with aneurysm should be compared; BAV appears as a feature of Loeys-Dietz syndrome and of the non-syndromic forms due to NOTCH1 (heavily calcified BAV) and MAT2A.

Source: Clinical Cardiogenetics, Table 19.5 [29]. The table does not define the percentages in parentheses; in the text of the same chapter, ACTA2 accounts for 12–21% and FBN1 for 3% of non-syndromic HTAD, consistent with reading them as the fraction of non-syndromic HTAD explained by the gene [29].

The distinction between Loeys-Dietz syndrome and Marfan syndrome rests on the triad of hypertelorism, cleft palate or bifid uvula and arterial tortuosity; lens dislocation is exclusive to Marfan syndrome, and most patients with Loeys-Dietz syndrome do not have long bone overgrowth [29]. In Marfan syndrome meeting the criteria, FBN1 sequencing detects the variant in about 90% [29]. In non-syndromic HTAD, the mean age at presentation of familial forms is younger than that of non-familial forms, but older than in Marfan syndrome, and dissection in childhood is rare; descending aortic aneurysms are associated mainly with atherosclerosis, which is an infrequent cause of ascending aortic aneurysm, so heritable forms should always be considered in this segment [29]. Thresholds and management depend on the HTAD gene.

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment that corrects the malformation and no drug that has been shown to prevent progression of aortic dilatation in BAV; the strategy rests on lifelong imaging surveillance, control of modifiable risk factors and prophylactic valve or aortic intervention at the appropriate time [7, 21]. The risk of dissection in BAV is lower than in Marfan syndrome, but dilatation implies a risk of acute dissection or rupture with a poor prognosis, and the high prevalence of BAV makes universal surveillance and preventive surgery costly for society [7]. Aortic surveillance continues even after valve replacement, because the aorta may continue to dilate [21, 23].

7.2. Blood pressure control and medical therapy

ACC/AHA 2022 recommends antihypertensive drugs in patients with thoracic aneurysm and mean systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg (1, B-NR), with a target of SBP ≤130 and DBP ≤80 mmHg and the possibility of considering SBP <120 mmHg if tolerated; a beta-blocker is reasonable to reach the target (2a, C-LD) and an angiotensin II receptor blocker (ARB) as an adjunct (2a, C-EO); there are no randomised trials on the blood pressure threshold for aortic outcomes [21]. A moderate- or high-intensity statin is reasonable when there is atherosclerosis (2a, C-LD) and may be considered without atherosclerosis (2b, C-LD) [21]. AATS 2018 recommends treating hypertension according to national or regional guidelines (I, C) and considers beta-blockers and renin-angiotensin-aldosterone system inhibitors for blood pressure control, with evidence extrapolated from connective tissue diseases, together with salt and weight reduction (IIa, C) [28]. The GeneReviews on HTAD adds counselling on smoking and dyslipidaemia as general measures in thoracic aortic disease [15]. The ESC 2020 adult congenital heart disease guideline states that there is no evidence for medical treatment of dilatation in bicuspid aortic disease and considers it reasonable to use beta-blockers or ARBs as first line when there is arterial hypertension; neither statins nor any other drug has been shown to delay progression of AS [4]. ESC 2014, now superseded, allowed beta-blockers with a root >40 mm (IIb, C) [24].

Medical therapy of bicuspid aortopathy was extrapolated from Marfan syndrome on the basis of histological similarities, without demonstrated efficacy in large BAV cohorts [7]. Beta-blockers may act by reducing mean arterial pressure and heart rate, but a 4D flow study showed no significant difference in aortic flows between treated and untreated patients with BAV [7]. ARBs were proposed for their inhibition of the TGF-β pathway mediated by the AT1 receptor, with promising results in small human studies not confirmed in the larger Marfan syndrome trials; angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to II, including the potentially beneficial AT2 pathway, and have not shown efficacy in bicuspid aortopathy [7, 93]. When beta-blockers or ARBs are used in a patient with BAV, the formal indication is blood pressure control; their use with the aim of slowing aortic dilatation in BAV is off-label and without randomised evidence of benefit, and the guidelines consulted do not establish specific doses for this purpose. The doses below are those of the trial protocols, cited only to describe the evidence.

Sources: [93–98].

The interpretation of these studies has limits: BICATOR, the only completed randomised trial, tested a statin and not an antihypertensive; the BAV Study ended with samples of 13 to 25 patients per arm and without power for any conclusion, and the registered unit of the outcome does not correspond to a diameter; the ACE inhibitor and paediatric studies are observational, and the Boston study, without a control, and the Naples study, with a control and no effect, reach opposite conclusions; and no study assessed clinical outcomes (dissection, surgery, death). The paediatric doses of atenolol and losartan above are those of an observational study, in off-label use. The absence of demonstrated effect is not proof of inefficacy of beta-blockers or ARBs in BAV, but it prevents presenting them as disease-modifying treatment [7, 94, 95].

7.3. Prophylactic aortic surgery

Prophylactic repair is the primary treatment to prevent death from type A dissection, and its timing is based on diameter thresholds that have become more individualised [5, 15]. Clinical Cardiogenetics (2020) reflected the recommendations then in force, citing the 2016 ACC/AHA clarification statement: elective surgery from 55 mm, from 50 mm with risk factors and from 45 mm when the valve is operated on for severe AS or AR; in that statement, the risk factors for 50–55 mm are a family history of dissection and growth ≥0.5 cm/year, in addition to low surgical risk, and systemic hypertension as a risk factor comes from ESC 2014 [7, 24]. ESC 2014 recommended surgery above 55 mm, above 50 mm with coarctation, systemic hypertension, a family history of dissection or growth >3 mm/year, and above 45 mm when valve replacement was planned (all I, C) [24]. Current guidelines diverge in the details; ESC/EACTS refers to the joint guideline of the ESC and the European Association for Cardio-Thoracic Surgery.

Sources: [4, 5, 21, 23, 28, 30]. For comparison, ESC 2020 recommends surgery in Marfan syndrome with a root ≥50 mm (I, C) or ≥45 mm with risk factors (IIa, C), in TGFBR1/TGFBR2 variants with a root ≥45 mm (IIa, C) and in Turner syndrome over 16 years of age with an ascending aortic size index >25 mm/m² and risk factors, among which BAV (IIa, C; IIb, C without risk factors) [4].

The rationale for the European thresholds is epidemiological: in mixed and BAV-only series, an ascending aorta of about 52 mm marks the increase in the risk of an acute event from about 1% to 4–5%, whereas the early mortality of elective proximal aortic surgery is 0.25–2%, so surgery in low-risk patients (<3%) with an ascending aorta >52 mm carries less risk than the natural history; at the root, the inflection point lies at 50 mm [5]. In a series of aortas ≥40 mm, the 5-year event risk was 1% at 50 mm and 0.1% at 40 mm, and in BAV above 50 mm the risk was 0.4% per patient-year versus 0.03% in the BAV population in general; a curvilinear ascending aortic length greater than 11.5 cm also increases the annual risk [5]. ACC/AHA 2022 describes «hinge points» of dissection risk between 5.25 and 5.75 cm, better survival with elective repair when the cross-sectional area/height is ≥10 cm²/m and limited data for 5.0–5.4 cm [21]. The difference between rapid growth defined as >0.5 cm/year (ACC/AHA 2020), ≥0.3 cm/year (ACC/AHA 2022), ≥3 mm/year (ESC 2024) and >3 mm/year (AATS 2018) is relevant in practice; the 2022 North American aortic guideline is later and specific, and the ACC/AHA 2025 adult congenital heart disease guideline adopted the value of ≥0.3 cm/year [21, 23, 31].

The type of surgery depends on the phenotype. In non-syndromic segmental aortopathy, liberal extension of resection to adjacent non-dilated segments is not justified: with the ascending phenotype and a normal or mildly dilated root or arch, replacing the tubular segment is sufficient; in the root phenotype with severe AR, especially in young patients, the earlier indication (50 mm) for root replacement favours valve repair in experienced centres [1]. The Bentall and De Bono operation (early 1970s; Dacron graft and/or mechanical valve) is the reference standard, and the valve-sparing techniques of David (reimplantation) and Yacoub (remodelling) avoid lifelong anticoagulation, with at least 90% of patients free from valve reoperation 10–15 years after surgery in a 20-year series by David himself, not specific to BAV [7]. The EACTS expert consensus of October 2026 on aortic valve repair and valve-sparing root replacement addresses echocardiographic assessment, patient selection and surgical techniques [99]. In aneurysms due to FBN1, SMAD3, TGFBR1, TGFBR2 and TGFB2, which almost always involve the root, GeneReviews recommends replacement of the root and ascending aorta; in non-syndromic HTAD without a known threshold in the family, Clinical Cardiogenetics proposes 4.5–5.0 cm in the ascending aorta and 5.5–6.0 cm in the descending aorta, guided also by the diameter at which relatives had complications [15, 29]. In valve surgery, the benefit of concomitant aortic repair is greatest in young, low-risk patients with the root phenotype and regurgitation, and may not be justified in high-risk patients with stenosis and moderate dilatation [21].

7.4. Valve intervention

The indications and timing of valve intervention for AS and AR in BAV are the same as for tricuspid valves, as is the choice of prosthesis type, with additional considerations specific to BAV [23]. In ESC/EACTS 2025, intervention is recommended in symptomatic severe high-gradient AS (I, B) and in asymptomatic severe AS with left ventricular ejection fraction (LVEF) <50% without another cause (I, B), and should be considered as an alternative to surveillance in asymptomatic severe AS with a normal exercise test, LVEF ≥50% and low risk (IIa, A); in severe AR, surgery is recommended if there are symptoms (I, B), if, in asymptomatic patients, the left ventricular end-systolic diameter is >50 mm, the indexed diameter >25 mm/m² or LVEF ≤50% (I, B), or in a patient undergoing coronary or ascending aortic surgery (I, C), and may be considered with an indexed diameter >22 mm/m², indexed end-systolic volume >45 mL/m² or LVEF ≤55% at low risk (IIb, B) [30]. The ESC 2020 adult congenital heart disease guideline, which applies to congenital valvular AS, has its own recommendations.

Source: ESC 2020 [4].

The same guideline allows balloon valvuloplasty in selected adolescents and young adults with a non-calcified valve, as a bridge to surgery in unstable patients or to postpone replacement in women with a suitable valve who wish to become pregnant; in calcified valves it indicates replacement; it notes that mechanical prostheses are more durable but require lifelong anticoagulation; and it suggests the Ross operation in women of childbearing age and to avoid anticoagulation, pulmonary homograft degeneration being the most frequent cause of reintervention, with percutaneous pulmonary valve implantation as an alternative [4]. After valve intervention, follow-up is at least annual [4].

In young people, valve prostheses have suboptimal results (growth), and anticoagulation for mechanical prostheses may prevent participation in sport; in children and young adults with isolated AS, balloon valvuloplasty and the Ross operation are the preferred options, and in adults valve replacement is preferred for its durability [7]. The ACC/AHA 2025 adult congenital heart disease guideline considers balloon valvuloplasty reasonable to postpone surgery in young adults with congenital valvular stenosis, a non-calcified valve and at most mild AR (2b, B-NR), and recommends that surgical and transcatheter options be reviewed by valve and adult congenital heart disease teams in shared decision-making (1, C-LD); options include repair, the Ross operation and a biological or mechanical prosthesis, and TAVI is an emerging option, useful as a temporising measure in young people (to reduce redo sternotomies, allow a pregnancy or await transplantation), with concerns about durability and anatomy [31].

In AR without stenosis, valve repair avoids anticoagulation, with success depending on leaflet quality (fibrosis, calcification) [7]. The main mechanism is prolapse of the conjoint cusp (or of one of the symmetric cusps in 2-sinus BAV), often with a dilated annulus (>25 mm), enlarged sinuses and a dilated sinotubular junction; repair combines plication of the free margins of the prolapsing cusps with an annuloplasty suture or ring, and possibly with stabilisation of the sinotubular junction, replacement of the ascending aorta or root reimplantation [1]. The closer the valve is to a symmetric 2-sinus BAV, the more feasible repair is, and a very asymmetric valve is treated as tricuspid; repair is successful more often in BAV than in the tricuspid valve, with a cumulative incidence of reoperation of 20% at 15 years when combined with root remodelling [1]. ESC/EACTS 2025 considers repair in selected patients with severe AR in experienced centres, if a durable result is expected (IIa, B), and identifies symmetry as a predictor of repairability [30]; ACC/AHA 2020 allows it in selected patients in a comprehensive valve centre (2b, C-LD) [23].

7.5. TAVI in bicuspid stenosis

The pivotal randomised trials of TAVI versus surgical valve replacement excluded BAV, and first-generation valves had more paravalvular regurgitation in BAV [23, 100]. The anatomical difficulties include asymmetric calcification, an elliptical annulus, a calcified raphe and non-standardised sizing, and data are scarce in 2-sinus BAV (Sievers type 0) [30]. ACC/AHA 2020 allows TAVI as an alternative to surgery in symptomatic severe AS in BAV after weighing risks, values and preferences, in a comprehensive valve centre (2b, B-NR) [23]. ESC/EACTS 2025 maintains surgical valve replacement as the primary treatment of bicuspid stenosis, especially in young patients, with aortopathy or with unfavourable morphology, recommends TAVI in patients aged ≥70 years only for the tricuspid valve with suitable anatomy (I, A) and allows that TAVI may be considered in severe bicuspid AS with increased surgical risk and suitable anatomy (IIb, B) [30]. The international consensus concludes that universal clinical equipoise between TAVI and surgery in bicuspid stenosis has not been reached [1]. The ESC 2020 adult congenital heart disease guideline, which predates ESC/EACTS 2025, considered that TAVI has no place in the treatment of congenital AS, except in very rare cases of high surgical risk when technically feasible [4].

These data must be read with caution: single-arm studies and registries select patients with favourable anatomy (in PARTNER 3, almost half of candidates were excluded), do not allow indirect comparison between devices or with surgery, and the bicuspid subgroup of NOTION-2, the only randomised data, has few events and wide confidence intervals that exclude neither harm nor absence of difference; absolute rates of permanent pacemaker (15–19% in the self-expanding studies) are relevant in young patients [101–104]. Randomised trials dedicated to BAV are ongoing: NCT06817148 (pilot, 250 patients, recruiting since January 2025), NCT07413965 (1,200 patients, starting July 2026, primary completion expected in 2032) and NCT06597188 (VitaFlow Liberty® versus surgical bioprosthesis, China, 452 patients), as well as studies of supra-annular sizing strategies in type 0 BAV (NCT04722796, NCT05511792), with no results located [111]. Results published in 2026 add signals in different directions: a meta-analysis of comparisons with surgery showed less major bleeding, acute kidney injury and length of stay with TAVI, more pacemakers, more coronary obstruction in type 0 and higher long-term mortality with aortopathy (>4.5 cm) and excess leaflet calcification [112]; another, of 7 mainly administrative studies (96,430 BAVs, 41,110 TAVIs), found no difference in early mortality, stroke or kidney injury [113]; in the international AD-HOC registry (980 low-risk patients), technical success was 94.7% below 69 years of age (n=113), with no severe prosthesis deterioration in the younger groups [114]; in the European CASPER registry (101 patients, 6 centres), a CT sizing algorithm advised undersizing in 38.6%, with a gradient of 8.3±4.3 mmHg, moderate paravalvular regurgitation in 6% and pacemaker in 25% at 30 days [115]; and in a Cologne cohort (92 patients; 78.8 years), mortality was 26.1% and stroke 14.1% over 2.9 years [116]. The PROSPERO-TAVI registry (NCT06248294) is studying progression of aortopathy after TAVI [117]. Observational studies registered on ClinicalTrials.gov include those of the BAVCon consortium (NCT01980797; 6,464 participants), Boston University BAV genetics (NCT01026571; 11,000), the University of Michigan registry (NCT01756222; 5,000 to 2040), the Leicester BRAVE study (NCT04514445; 700), a French cohort (NCT03139786), a Chinese cohort (NCT06802016), genetic prediction of early calcification (NCT06153407), exome sequencing in BAV in Marseille (NCT02899624, status unknown) and a Cedars-Sinai TAVI registry (NCT03836521; 2,000), as well as the vitamin K2 trial in bicuspid AS (NCT02917525, status unknown) and the CONTOUR standardised repair trial (NCT06869954) [111].

7.6. Regulatory status

The chronology of FDA decisions in the PMA files of the two devices most studied in BAV is as follows.

Source: FDA PMA database and instructions for use [32, 33].

The current instructions for use of the two devices state that there are limited clinical data in congenital BAV in patients at low surgical risk, that anatomical characteristics should be considered and that age should be weighed because long-term durability is not established, and that safety and efficacy are not established in the congenital unicuspid aortic valve; the Evolut labelling warns about root injury and prosthesis deformation in calcified bicuspid anatomy, and the SAPIEN 3 trial in asymptomatic severe AS excluded the unicuspid valve and bicuspid valves with unfavourable characteristics (ascending aorta >4.0 cm, bulky calcification of the outflow tract or raphe) [32, 33]. A search of the PMA database found no supplements mentioning BAV for Navitor (Abbott), whose labelling was not read; the 2025–2026 PMA decisions did not change the bicuspid precaution, and no BAV-specific FDA regulatory decision was located in the window from October 2025 to October 2026; a negative search does not prove that none exists [32, 33]. The notified body certificate and the European instructions for use were not consulted, so the European status rests on a manufacturer press release confirmed by the specialist press; the same source reports CE marking of SAPIEN 3 for low risk in November 2019, without mention of BAV [118, 119].

7.7. Prevention of infective endocarditis

AHA 2021 maintained the recommendation against dental antibiotic prophylaxis in patients at low or moderate risk, the category that includes native BAV; prophylaxis is reserved for the highest-risk categories, among which prosthetic valves and prosthetic material, previous endocarditis, some congenital heart diseases and heart transplant recipients with valvulopathy [120]. The same statement reports data from a Spanish multicentre study (3,208 patients), in which BAV and mitral valve prolapse had intracardiac complications and need for surgery similar to those of the high-risk group but lower mortality, and data from the United Kingdom in which mortality from congenital valve anomalies was similar to that of the high-risk group [120]. ESC 2023 classifies congenital valve anomalies, including BAV, as intermediate risk for endocarditis; antibiotic prophylaxis is not routinely recommended and may be considered individually, and general dental and skin hygiene measures apply to high and intermediate risk [68]. After valve replacement with a prosthesis, the patient moves to the high-risk category [68, 120].

Source: ESC 2023, Recommendation Table 1 [68].

For BAV, this means that the native valve has no indication for routine prophylaxis, but surgical or transcatheter valve replacement, repair with prosthetic material and the Ross operation with a homograft place the patient in the high-risk category, with prophylaxis I, C [68]. The ESC 2020 adult congenital heart disease guideline also reserves prophylaxis for high risk [4]. The divergence between the two societies is mainly one of framing (moderate versus intermediate risk with the possibility of an individual decision), and both converge on oral and skin hygiene, justified by the lifetime incidence of endocarditis of 6% in a community cohort [26, 68, 120].

7.8. Physical activity, sport and driving

Between 5% and 8% of sudden deaths in sport in athletes under 40 years of age are due to AS and/or rupture of a thoracic aneurysm, often associated with BAV [7]. The ESC 2020 sports cardiology data show that athletes with BAV have aortic growth of 0.11±0.59 mm/year at the sinuses and 0.21±0.44 mm/year in the proximal ascending aorta, similar to that of non-athletes with BAV, with no correlation between aortic dimensions and training duration in 58 athletes; in 49 published cases of exercise-related dissection (42 type A), 26 occurred during weightlifting, and 4.1% of 615 type A dissections were related to sport [75]. Without aortopathy, exercise recommendations are those for tricuspid valve dysfunction, and exercise testing with assessment of the blood pressure response is recommended before starting sport [75].

Source: ESC 2020, Table 14 [75].

The ESC 2020 adult congenital heart disease guideline recommends avoiding isometric exercise and high-intensity sport in severe AS, symptomatic or not, and in moderate AS due to BAV with a dilated aorta, allows more intense activity in mild and moderate AS and advises prior exercise testing [4].

The 2015 AHA/ACC recommendations for competitive athletes, reproduced by Clinical Cardiogenetics, used classes and levels of evidence [7, 74, 121].

Source: AHA/ACC 2015, Task Force 7 [121].

In the same 2015 series, Task Force 5 estimated BAV at 1.5–2.0% of the population and AS as the cause of less than 4% of sudden deaths in young athletes, and recommended annual assessment (I, C), all sports in mild AS with a normal maximal exercise response (IIa, C), IA, IB and IIA sports in moderate AS with an exercise test at competition level without symptoms, ST depression or ventricular tachyarrhythmias and with a normal blood pressure response (IIa, C), and no competitive sport, except possibly IA, in asymptomatic severe AS (III, C) and none in symptomatic severe AS (III, C) [74]. For athletes with BAV without stenosis it recommended an annual physical examination to detect a new murmur and echocardiography in all patients with BAV for valve function and the dimensions of the sinuses and ascending aorta, noting that it is not known whether restricting activity reduces risk or growth [74].

The 2025 AHA/ACC statement replaced the 2015 recommendations with clinical considerations without classes, based on shared decision-making [73].

Source: AHA/ACC 2025, Table 10 [73].

The 2025 statement uses absolute diameters, because there are no outcome data for z-scores or sex-specific criteria, allows adjustment in very tall or short athletes and in Turner syndrome, and indicates that an aorta >42 mm in men and >40 mm in women is rare in young athletes, whereas 1–2% of athletes with a tricuspid valve without HTAD have an aorta ≥40 mm; most acute aortic syndromes in registries do not occur during exercise [73]. In BAV, AR is generally well tolerated, whereas severe AS carries a high risk of exercise-related cardiac arrest; in moderate AS, participation is reasonable with shared decision-making if the athlete is asymptomatic and the exercise test at competitive level is normal; in asymptomatic moderate or severe AR, the athlete may participate with normal systolic function and ventricular dimensions or those consistent with athletic remodelling, without pulmonary hypertension and with normal exercise tolerance, and severe AR with an end-systolic diameter >50 mm or end-diastolic diameter >70 mm requires further assessment; anticoagulated carriers of a mechanical prosthesis should avoid collision sports [73]. In athletes aged 35 years or more with unexplained dilatation, endurance sports are reasonable below 45 mm and may be considered at 45–49 mm with shared decision-making [73]. The ACC/AHA scientific statement of September and October 2026 for tactical athletes (firefighters, law enforcement, military personnel) considers participation in all occupational tasks reasonable in BAV with dilatation of 40–44 mm without additional risk factors, requires tactical clinical management and specialist consultation at 45–49 mm for tasks above low strength and low endurance, allows unrestricted return after aneurysm resection for non-syndromic, uncomplicated bicuspid aortopathy, limits HTAD to IA tasks and notes that more than 20% of older endurance athletes have a root or ascending aorta >40 mm due to exercise-induced remodelling [122]. In summary, the 2015 recommendations restricted from 40–42 mm in men and 36–39 mm in women and excluded all competitive sport above 45 mm, the 2025 recommendations allow participation with shared decision-making at 40–44 mm and, in selected cases, from 45 mm, and ESC 2020 stratifies by <40, 40–45, 45–50 and >50 mm [73, 75, 121]. AATS 2018 recommends avoiding heavy weightlifting and isometric competitive sport when the ascending aorta exceeds 45 mm (I, B) and avoiding efforts with a Valsalva manoeuvre when the aneurysm is at or near the surgical threshold (IIa, C), and considers that driving private vehicles should be barred with an ascending aorta >6.0 cm and professional driving with >5.5 cm (IIa, C) [28]. Exercise has important benefits compared with a sedentary lifestyle, and some form of physical activity is advisable in most patients [7].

7.9. Pregnancy and lactation

In most women, BAV does not cause major problems in pregnancy; published complications are probably over-represented because uneventful pregnancies are under-reported, an argument supported by a Polish study of 89 patients with BAV [7]. A woman with congenital heart disease who is planning pregnancy should be followed in an adult congenital heart disease clinic, with assessment of the foreseeable effect of pregnancy and an offer of fetal echocardiography [77]. Pregnancy-related type A dissection in isolated BAV has rarely been described: in 88 women with BAV without dilatation there were no dissections in 186 deliveries, and in 49 patients with moderate dilatation (median 42 mm) there were none either, but there are no data above 4.5 cm [21]. ESC 2025 considers the risk of aortic events low with an aorta <45 mm, data limited between 45 and 50 mm, and the risk higher in the root phenotype [92]. In the modified World Health Organization classification (mWHO 2.0), BAV with an aorta <45 mm is class II–III, dilatation of 45–50 mm class III and dilatation >50 mm class IV, in which pregnancy is contraindicated [92]. The ESC 2020 adult congenital heart disease guideline, adapted from ESC 2018, already placed dilatation of 45–50 mm in BAV in mWHO III (maternal cardiac events in 19–27%) and dilatation >50 mm in mWHO IV (40–100%, pregnancy to be avoided), as well as symptomatic severe AS and severe (re)coarctation, with asymptomatic severe AS in mWHO III; it contraindicated pregnancy in symptomatic severe AS (valvuloplasty or surgery before conception), allowed it in selected patients with asymptomatic severe AS and a normal exercise test, and noted that BAV-associated dilatation may appear and progress during and after pregnancy [4]. Severe or symptomatic AS before pregnancy is associated with a risk of about 1 in 4 of heart failure during gestation (ROPAC registry data on moderate and severe AS, not exclusive to BAV); symptomatic severe AS should be treated before pregnancy and intervention should be considered in asymptomatic severe AS with systolic dysfunction or limitation on exercise testing [92]. Aortic dissection in pregnancy and the postpartum period occurs in 5.5 per million women, versus 1.4 per million in the equivalent period one year later, and most peripartum dissections occur in the 3rd trimester and up to 12 weeks after delivery [15, 92].

Sources: [15, 21, 92].

The main divergence is the ESC 2025 threshold of 45 mm for BAV with the root phenotype or a family history, absent from ACC/AHA 2022, which recommends pre-pregnancy surgery from 5.0 cm without distinction of phenotype [21, 92]. In the ROPAC registry, birth weight was 2,960 g (2,358–3,390) with a beta-blocker and 3,270 g (2,750–3,570) without (p=0.25), and ROPAC III showed significantly lower birth weight with a beta-blocker, which justifies monitoring of fetal growth [21, 92]. Dilatation >4.0 cm in a woman of childbearing age is uncommon and should prompt assessment for genetic aortopathy [21]. The sources consulted do not specifically address lactation in BAV; GeneReviews refers to the MotherToBaby service for information on drugs in pregnancy [15].

7.10. Perioperative care, transition and follow-up after intervention

Valve replacement does not eliminate aortic risk: after isolated valve replacement in 1,286 patients (median 12 years), dissection occurred in 1%, ascending aortic replacement in 0.9% and progressive enlargement in 9.9% [21, 23]. A 2026 Portuguese meta-analysis (15 studies) found no significant difference between BAV and the tricuspid valve after valve intervention in ascending aortic growth (difference 0.15 mm/year; 95% CI −0.03 to 0.33; I² 82.6%), dissection (RR 1.34; 0.63–2.83) or reintervention (RR 0.95; 0.56–1.61) [123], and after balloon-expandable TAVI ascending aortic growth was 0.37 mm/year in BAV and 0.31 mm/year in the tricuspid valve [109]. Even so, guidelines recommend maintaining lifelong aortic surveillance when the root or ascending aorta measures ≥4.0 cm (ACC/AHA 2020 2a, B-NR; ACC/AHA 2022 1, B-NR) [21, 23]. AATS considers that surveillance recommendations apply to native BAV and after valve replacement (I, B), allows a baseline CT or MR angiography after surgery (IIb, C) and recommends imaging of the whole aorta every 3–5 years by CT or MRI when residual dilatation persists after repair (IIa, B) [28]. Before cardiac surgery with a root or ascending aorta of 40–44 mm on TTE, AATS recommends MR or CT angiography to plan the extent of surgery (I, C) [28]. ACC/AHA 2025 recommends that interventions on the congenital aortic valve be performed by surgeons experienced in adult congenital heart disease and decided jointly, based on a randomised trial in patients without congenital heart disease in which shared decision-making improved information and reduced anxiety and depression [31]. The transition from paediatric to adult cardiology is particularly relevant in complex valvulo-aortopathy, diagnosed mainly in childhood and with excess mortality, and in young people who have undergone valvuloplasty or the Ross operation, who need planned reinterventions [7, 26, 31].

7.11. Developments in the last twelve months

7.12. Summary of divergences between guidelines

The main divergences concern the surgical threshold in the root phenotype (50 mm with a class I recommendation in ESC 2024, a risk factor for surgery at 50–54 mm in the North American guidelines), the threshold in the low-risk ascending phenotype (52 mm in ESC 2024), the definition of rapid growth (0.3 to 0.5 cm/year), the area/height index (10 versus 13 cm²/m), screening for intracranial aneurysms in coarctation (I, B in AATS 2018; no evidence in favour in ESC 2024), the indication for genetic testing (not indicated in isolated BAV by ESC 2024; genetic evaluation in BAV with HTAD or Loeys-Dietz features by ACC/AHA 2022), the strength of the family screening recommendation (section 8.2), the pre-pregnancy surgical threshold with risk factors (45 mm only in ESC 2025), the role of TAVI (2b in ACC/AHA 2020 in symptomatic AS, IIb in ESC/EACTS 2025 only at increased surgical risk, no place in congenital AS except in very rare cases in ESC 2020) and sports participation with an aorta of 40–45 mm (restricted in AHA/ACC 2015, shared decision-making in AHA/ACC 2025) [4, 5, 21, 23, 28, 30, 73, 92, 121]. The ESC 2020 adult congenital heart disease guideline, with thresholds of 50 mm with risk factors and 55 mm (both IIa, C), is weaker than ESC 2024 (55 mm I, B; 50 mm in the root phenotype I, B; >52 mm in the low-risk ascending phenotype IIa, B), which prevails as regards the aorta [4, 5]. In the internal discrepancy of ACC/AHA 2020 between the table (>5.5 cm) and the supporting text (≥5.5 cm), later guidelines (ACC/AHA 2022, ESC 2024) use ≥55 mm [5, 21, 23].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

In most families, BAV behaves as a multifactorial trait with high heritability, and risks for relatives are empirical; in a minority there is autosomal dominant inheritance with incomplete penetrance and variable expressivity, in which obligate carriers may have BAV, aortic dilatation, both or neither [7, 21]. Affected relatives may have lesions different from that of the proband (BAV, coarctation, HLHS, VSD, ASD, isolated aortic dilatation), because these lesions share developmental mechanisms [3, 19, 44].

The empirical tables of the Oxford Desk Reference do not distinguish isolated BAV, and the offspring data apply to congenital heart disease as a whole [77]. The full table of recurrence risks for isolated non-syndromic defects from the same book, adapted from Burn and Goodship (2001), is useful when the relative has a lesion other than BAV.

Source: Oxford Desk Reference, Table 2.8 [77]. The printed legend repeats «(F)» for both parents; from the text on the same page, the first offspring column corresponds to the father and the second to the mother. The text gives 4.5% for the offspring of a mother with tetralogy of Fallot (the table gives 4.7%) and about 8% for both parents in atrioventricular septal defect, and the table has no specific row for BAV [77]. These risks do not apply when the defect segregates as a Mendelian trait in the family, in which case counselling follows the observed inheritance pattern; monozygotic twins have a risk of congenital heart disease about 3 times higher than singleton pregnancies and dizygotic twins about 1.3 times, and miscarriage is more frequent when the mother has congenital heart disease (20% versus 10% when the father is affected) [77]. The male predominance is repeated in relatives (9.2% versus 3.5% in the Spanish cohort), although AATS states that men and women are similarly affected in families [20, 28].

8.2. Clinical screening of relatives

Echocardiographic screening of first-degree relatives is recommended by all guidelines, with variable strength.

Sources: [4, 5, 21, 23, 28, 30, 31].

Clinical Cardiogenetics attributed to the ESC a IIa, C recommendation for echocardiography in all first-degree relatives, but cited the 2010 North American thoracic aortic disease guideline; class IIa, C belongs to the ESC 2014 aortic diseases guideline («screening of first-degree relatives should be considered», without data on effectiveness or cost-effectiveness), and ACCF/AHA 2010 had a class I, level C recommendation to evaluate first-degree relatives of patients with BAV, with early-onset thoracic aortic disease and few risk factors or with familial thoracic aneurysm and dissection for the presence of BAV and asymptomatic aortic disease [7, 24, 34]. Both have been superseded by the guidelines above. The ESC 2020 adult congenital heart disease guideline, without a class in the table, considers echocardiographic screening of first-degree relatives recommended and appropriate especially in boys, athletes and when hypertension is present [4]. ESC 2024 indicates that, in 5–15% of cases, at least one first-degree relative has BAV or ascending aortic dilatation and that the root phenotype and AR in the proband predict dilatation in relatives [5]. Cost-effectiveness is poorly known: the analysis by Hales and Mahle, on echocardiographic screening of siblings of children with BAV, estimated a cost of 74,884 dollars per life-year saved (2012 value), a result that does not transfer directly to relatives of adults, ACC/AHA 2022 considers screening cost-effective on the basis of a cited analysis, and ACC/AHA 2020 noted the scarcity of data [7, 21, 23]. The age at which screening should begin is undetermined (as early as possible or from 18 years) [5, 7].

Relatives with BAV move to standard surveillance (section 11). Relatives with a tricuspid valve may also have dilatation: 9.6% in the Spanish cohort (root phenotype 2.7% and tubular 6.9%), associated with hypertension (OR 4.48; 95% CI 2.51–7.99) and valve regurgitation (OR 5.87; 1.37–25.16) [20]. There are no formal recommendations for these relatives; Clinical Cardiogenetics advises follow-up every 3–5 years, a view that contrasts with the single echocardiogram of ACC/AHA 2025 and that applies mainly to relatives with dilatation or risk factors [7, 31]. When a relative has BAV and/or dilatation, cascade assessment extends to the remaining relatives, and as some families have dilatation without BAV, CT or MRI should be used if TTE assesses the ascending aorta poorly [21]. In families with HTAD of unknown cause, GeneReviews recommends aortic imaging of all first-degree relatives, and imaging of the head and neck if there is a family history of intracranial or cervical aneurysms [15]. For families with thoracic aneurysm or dissection without a molecular diagnosis, applicable to families with BAV and aneurysm, Clinical Cardiogenetics reproduces the Dutch consensus protocol of Verhagen and colleagues (2018), summarised in the following table; it is an expert consensus predating current guidelines [29].

Source: Clinical Cardiogenetics, Figure 19.18 [29]. The authors justify the ages by the rarity of clinically relevant disease below them and point out the psychological impact of screening; they recommend regular imaging of all first-degree relatives in families without an identified variant and pre-test counselling on risks, benefits, limitations and ethical, legal and social implications before genetic testing [29].

8.3. Cascade molecular testing

Cascade testing is indicated only when the proband has a pathogenic or likely pathogenic variant; for a VUS it is not advisable, although segregation analysis may help to reclassify it [7]. In HTAD with a known variant, GeneReviews recommends testing parents, siblings, children and other at-risk relatives, with gene-based management for carriers and discharge from specific aortic surveillance for confirmed non-carriers [15]. The sources consulted do not define whether discharge from surveillance applies to relatives who do not carry a BAV variant, where incomplete penetrance and the polygenic background make echocardiography the examination that directly answers the clinical question. In the clinical case in section 10.1, the 11 relatives without the NOTCH1 variant had no cardiovascular anomalies [61].

8.4. De novo variants and mosaicism

If the variant is not detected in either parent (with confirmed paternity), it may have arisen de novo or there may be germline or somatic mosaicism in a parent, which testing in leucocytes may not detect; the risk to siblings is 50% if a parent is a carrier and about 1% if the variant was not detected in the parents, and each child of a carrier has a 50% probability of inheriting the variant [15]. A carrier parent may have no manifestations because of reduced penetrance and should therefore be studied by echocardiography even if asymptomatic [15, 50].

8.5. Prenatal diagnosis, preimplantation testing and conception

Specialist fetal echocardiography may be offered in pregnancies of couples with a history of left-sided heart disease (section 5.9), and prenatal molecular diagnosis and preimplantation genetic testing depend on a familial P/LP variant, with predictive value limited by incomplete penetrance [7, 44]. Preconception counselling of a woman with BAV includes the recurrence risk, genetic testing when indicated, prior aortic imaging and discussion of maternal complications, with a multidisciplinary cardiology and maternal-fetal medicine team (section 7.9) [15, 92]. Dilatation >4.0 cm in a young woman should prompt assessment for genetic aortopathy before pregnancy [21].

8.6. Counselling of minors and content of counselling

In children, echocardiography directly answers the clinical question, because BAV is visible from the neonatal period [22]; paediatric screening of siblings and children does not depend on molecular testing. In heritable aortic diseases, predictive testing in minors is accepted when the disease begins in childhood and preventive measures exist (Marfan syndrome, Loeys-Dietz syndrome and other HTAD), whereas in non-syndromic HTAD, with less obvious medical benefit in childhood, it is usually deferred to adulthood to protect autonomy, always with psychosocial support [29]. For BAV genes, the sources consulted do not establish a minimum age; the decision follows clinical benefit, which lies mainly in guiding echocardiographic surveillance. Counselling should explain that most cases have no identifiable monogenic cause, that a negative test does not exclude familial risk, that carriers of SMAD6 variants should also be assessed for craniosynostosis and radioulnar synostosis, that GATA6 carriers need glycaemic and pancreatic monitoring and NKX2-5 carriers serial ECGs, and that in NOTCH1 families carrier relatives may have heart defects other than BAV [1, 6, 50]. It should also address lifelong surveillance, warning signs of dissection and endocarditis, oral hygiene, physical activity appropriate to aortic diameter and pregnancy planning [21, 68, 75, 92].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The values of 1–2% cited in several documents are higher than that of the Copenhagen study, the only large population echocardiographic screening study in the sources consulted, which found a value below 1% [22, 37]. BAV is the most common congenital heart defect, and in the past its complications were responsible for more mortality and morbidity than all other congenital heart defects combined [7]. Orphanet classifies BAV as «not rare in Europe» (ORPHA:1244) and has no epidemiological data recorded for this entity or for familial BAV [2, 11]. For the entities in the differential, Orphadata records 7 cases or families of patent ductus arteriosus–BAV–hand anomalies syndrome (prevalence class <1/1,000,000, validated), 398 cases or families and a point prevalence of 1–9 per 1,000,000 (mean value 0.44 per 100,000) for Adams-Oliver syndrome across all genes, and 22 cases or families with an unvalidated prevalence class <1/1,000,000 for familial thoracic aortic aneurysm and dissection; this last value is an administrative record that contradicts the clinical proportion of about 20% of patients with aneurysm or dissection who have an affected relative, and should not be read as a prevalence [12–14, 29]. As a contextual reference, structural congenital heart disease occurs in 7 per 1,000 live births [77].

9.2. Sex

The male:female ratio is 2–3:1 in the guidelines (3:1 in ACC/AHA 2020; 2:1 to 4:1 in ESC 2014) and 2.1:1 in the Danish neonatal cohort, in which 51.7% of the newborns studied were boys [21–24]. In clinical cohorts, the proportion of men was 65% in Olmsted County, 68% in Toronto, 72.0% in the international registry and 77% in a genetics cohort of 100 patients, and in the German sporadic BAV cohort 549 of 740 patients were men [45, 56, 64, 69, 70]. In relatives screened in Spain, BAV was more frequent in men (9.2% versus 3.5%) [20]. The male predominance and the frequency in Turner syndrome support the hypothesis of a BAV gene on the X chromosome [7]. The phenotype also differs by sex: in the Polish RE-BAV registry (808 adults), women had more of the extended phenotype and men more of the root phenotype and moderate to severe AR, with differences depending on the indexing method [65].

9.3. Geography and ancestry

The available data come mainly from the USA (Olmsted County, Minnesota; GenTAC registry; Million Veteran Program; TAVI studies), Canada (Toronto; Quebec), Northern and Western Europe (Denmark, Germany, Spain, United Kingdom, Nordic countries) and, to a lesser extent, Asia (Chinese clinical case and TAVI trials in China) [10, 20, 22, 45, 51, 61, 69, 70, 104]. Right-left fusion is the most common phenotype in American, European and Asian populations, but right-non-coronary and left-non-coronary fusions are more prevalent in Asian populations, and African-American patients have a lower prevalence of BAV and aortopathy [1]. The Thériault GWAS describes a lower incidence of BAV in African populations and included only participants of European ancestry, and the Million Veteran Program GWAS included individuals genetically similar to European, African, admixed American and East Asian reference populations, but with much smaller effective sizes in the non-European groups (for example 159 in East Asia) [10, 63]. The sources consulted do not describe founder variants in BAV. The EBAV cohorts were 98% European [9]. Iberian data include the Spanish family screening cohort, the BICATOR trial, also Spanish, and a 2026 Portuguese meta-analysis (Lisbon), which pooled 15 international studies on aortic growth after valve intervention, without data on patients identified as Portuguese [20, 94, 123]; an author from Porto (Cerqueira) is part of the 2026 EACTS consensus on valve repair [99]. From Brazil, the multicentre TAVI registry (25 centres, 2009–2021) describes 111 patients with BAV among 2,426 treated (4.6% of the series), with in-hospital mortality of 7% versus 3% in matched pairs with a tricuspid valve (p=0.21) and a reduction in mortality over the period; it is a series of patients with AS undergoing TAVI, not a prevalence estimate [110]. Central Europe has data in the Polish RE-BAV registry [65]. The sources consulted do not describe the population prevalence of BAV in Portugal or Brazil.

9.4. Special populations

In women with Turner syndrome, BAV is much more frequent than in the general population and aortic assessment uses body size indices [1, 78]. In children, complex forms are more frequent, MRI may be preferred to CT and measurement uses z-scores [1, 7]. In athletes, BAV without aortopathy follows the general sports recommendations, but exercise-related dissection has been described mainly during weightlifting (section 7.8) [75]. In pregnant women, the risk depends on the diameter, the phenotype and AS (section 7.9) [92]. In older people, BAV is a frequent cause of calcific stenosis (up to 20% of patients aged 80 years or more undergoing aortic valve surgery) and the distinction from acquired fusion is difficult [1]. In Down syndrome, right-non-coronary fusion predominates [1]. Patients with coarctation, Shone complex or HLHS in the family belong to a group with greater clustering of left-sided lesions [28, 44].

9.5. European Reference Networks and patient associations

ERN GUARD-Heart brings together European centres for rare and complex heart diseases, including congenital heart disease, and VASCERN has a working group dedicated to heritable thoracic aortic diseases (coordinated at Radboud UMC, Netherlands, and co-coordinated at AP-HP Bichat, Paris), with clinical pathways for patients and consensus statements; the group's page does not mention BAV, and its relevance is limited to BAV with familial aortopathy or suspected HTAD; the genetic testing indication flowchart in section 5.6 was adapted from the VASCERN clinical pathway [29, 35, 36]. Patient organisations with information on aortic disease and BAV include the John Ritter Foundation for Aortic Health (USA), Aortic Dissection Awareness UK & Ireland, the Marfan Foundation (which includes familial aortopathies), the Genetic Aortic Disorders Association of Canada and the American Heart Association and MedlinePlus pages on aortic aneurysm [15, 126, 127]. For families with congenital heart disease, the Oxford Desk Reference indicates the Children's Heart Federation (United Kingdom; http://www.chfed.org.uk) and, for HLHS, Little Hearts Matter (Birmingham; https://www.lhm.org.uk) [44, 77]. The sources consulted did not identify a patient association dedicated exclusively to BAV with an accessible website, nor specific Portuguese or Brazilian associations.

10. Illustrative Clinical Case

10.1. Family with calcified BAV and a NOTCH1 nonsense variant

Chen and colleagues (2025) described a Chinese family with BAV over four generations and a novel NOTCH1 nonsense variant [61]. The proband (IV1) was born at 37 weeks and 6 days of gestation, weighing 2,790 g and measuring 48 cm, and had neonatal asphyxia; she presented with respiratory distress, dysphagia, choking, recurrent fever and seizures, and bedside echocardiography showed a persistent left superior vena cava and a dilated coronary sinus, without BAV; she died at one month of age [61]. The mother (III4, born in 2000) had undergone surgery for patent ductus arteriosus at 4 years of age and was diagnosed with BAV at 8 years; an echocardiogram 12 years earlier had shown AS (velocity 391 cm/s, mean gradient 32 mmHg) and mitral stenosis, and reassessment during her daughter's admission showed BAV with worsening AS (peak velocity 513 cm/s, mean gradient 66 mmHg), aortic valve calcification and mitral stenosis [61]. The maternal grandfather (II7, BAV diagnosed at 44 years) and great-uncle (II9, BAV at 40 years) had BAV with stenosis and calcification, and the great-grandmother (I2), already deceased with no DNA available, had BAV [61].

Exome sequencing of the proband, confirmed by Sanger sequencing, identified the variant NM_017617.5:c.2266G>T p.(Glu756Ter) in exon 14 of NOTCH1 (NC_000009.12:g.136513479C>A on GRCh38; NP_060087.3:p.(Glu756Ter), MANE Select transcript), present in the heterozygous state in the proband, mother, grandfather and great-uncle, and absent in the 11 tested relatives without cardiovascular anomalies [49, 61]. The authors classified it as pathogenic according to the ACMG/AMP criteria (PVS1, PM2, PP1 and PP4) and proposed haploinsufficiency through nonsense-mediated mRNA decay or a truncated protein, with a predicted loss of about 1,800 amino acids; a second variant, ATAD3A NM_018188.5:c.1517A>C p.(Gln506Pro), was classified as a VUS and did not segregate with the phenotype [61]. Figure 1 of the article shows the electropherogram, the pedigree and the mother's echocardiogram (https://pmc.ncbi.nlm.nih.gov/articles/PMC12482243/figure/Fig1/), and Figure 2 the predicted structure and domains of NOTCH1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12482243/figure/Fig2/) [61].

The case illustrates three points of this article: complete segregation in the tested relatives with variable intrafamilial expressivity (calcified and stenotic BAV in the adults, a systemic venous anomaly without BAV in the newborn), the early valve calcification characteristic of NOTCH1 and the value of a multigenerational pedigree [37, 61]. Attribution of the neonatal manifestations (asphyxia, seizures, death) to the NOTCH1 variant was not demonstrated, and the authors propose a possible relationship between the persistent left superior vena cava and the Adams-Oliver spectrum as a hypothesis. The authors' recommendation to test NOTCH1 in all at-risk relatives applies to a family with a known pathogenic variant and not to genetic testing in isolated BAV, which guidelines do not recommend routinely (section 5.6) [5, 61]. The article does not describe the mother's treatment; with AS with a mean gradient ≥40 mmHg, her management would follow the intervention criteria for severe AS and, in a young woman, planning for a possible pregnancy (section 7) [30, 92].

10.2. Calcified BAV with ascending aortic aneurysm and a SMAD6 variant

Park and colleagues (2019) described a 42-year-old Korean man seen at Samsung Medical Center for ascending aortic dilatation [62]. Echocardiography showed BAV with severe valve calcification, and CT angiography an ascending aorta of 5.5 cm with dense calcification of the valve; at the root, echocardiography measured an annulus of 2.5 cm, sinuses of 3.1 cm and a sinotubular junction of 3.3 cm [62]. His father had died at 69 years of age of bladder cancer, with no known cardiovascular disease, and there were no other relatives with cardiovascular disease [62]. Exome sequencing, filtered for 20 BAV genes, identified the in-frame duplication NM_005585.5:c.1168_1173dup, NP_005576.3:p.(Gly390_Ile391dup), in the MH2 domain of SMAD6 (NC_000015.10:g.66781212_66781217dup on GRCh38, normalised in VariantValidator to the MANE Select transcript), absent from 1000 Genomes, gnomAD and the Korean KRGDB database, and absent in the mother and brother, both without BAV or aneurysm; the variant may have arisen de novo or been inherited from the father, who was not tested [49, 62]. In C2C12 cells, the variant reduced inhibition of BMP2-induced SMAD1/5/8 phosphorylation, BRE-luc reporter activity and alkaline phosphatase, as did the p.(Cys484Phe) control from Tan 2012 (NM_005585.5:c.1451G>T) [38, 62]. In the authors' review, most of the 13 previous cases of BAV with a SMAD6 variant, from two studies, had thoracic aneurysm or coarctation [62]. Figure 1 of the article shows the CT angiography with the aneurysm and valve calcification, the pedigree and the electropherogram (https://pmc.ncbi.nlm.nih.gov/articles/PMC6503022/figure/mgg3620-fig-0001/), and Figure 2 the BMP signalling assays (https://pmc.ncbi.nlm.nih.gov/articles/PMC6503022/figure/mgg3620-fig-0002/) [62].

The article does not describe the surgical management or the outcome. With an ascending aorta of 5.5 cm, the patient would be at the general surgical threshold of all guidelines (section 7.3), and severe valve calcification would indicate assessment of AS and of possible combined valve and aortic surgery [5, 21, 30]. The case illustrates severe valve calcification associated with loss of inhibition of the BMP pathway, the presentation of a SMAD6 variant without a family history, consistent with frequent transmission from unaffected parents, and the need to assess the carrier for craniosynostosis and radioulnar synostosis and to offer echocardiography to relatives, regardless of the molecular result (section 8) [6, 62]. The authors classified the variant as likely pathogenic according to the 2015 ACMG/AMP criteria, on the basis of the deleterious effect demonstrated in vitro, absence from population databases and the change in protein length due to an in-frame duplication in a non-repetitive region; there are no segregation data to support it, so cascade testing of relatives would serve mainly to guide surveillance and does not replace echocardiography [62].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In typical valvulo-aortopathy, life expectancy is similar to that of the age- and sex-matched population, despite high cumulative morbidity: in Olmsted County, 20-year survival was 90% in patients with minimal dysfunction, equal to that of the population, and the typical form had survival equal to that of the Minnesota population, whereas the complex form had a relative excess mortality of 2.25 [1, 26, 69]. Cumulative morbidity from birth to 90 years was 86%, with valve surgery in 68.5%, aneurysm in 75.4%, aortic surgery in 27%, endocarditis in 6% and dissection in 1.6% [26]. The 2025 meta-analysis of BAV unrepaired at diagnosis (5,819 patients) confirmed survival similar to that of the general population (84.3% at 10 years and 76.0% at 15 years; HR 1.15; 95% CI 0.86–1.55), with 70.0% free from cardiac surgery at 10 years and dissection at 0.06 per 100 patient-years [27], and the ESC 2020 adult congenital heart disease guideline summarises cardiac mortality at 0.3% per patient-year [4]. Predictors of events include age (≥50 years in Olmsted County; >30 years in Toronto), valve degeneration at diagnosis, moderate to severe AS or AR and a baseline ascending aortic diameter ≥40 mm for aortic surgery [69, 70]. The risk of dissection depends mainly on diameter, the root phenotype, coarctation, family history and growth, and is very low in patients without dilatation [5, 21, 66]. After isolated valve replacement, survival and the occurrence of aortic events vary between series (section 3.7), and patients operated on for AR with the root phenotype have the highest late aortic risk [21, 28].

11.2. Surveillance

Surveillance recommendations also apply after valve replacement when the root or ascending aorta measures ≥4.0 cm [21, 23, 28]. Intervals should be individualised according to cause, diameter, growth rate, proximity to the surgical threshold, age and family history; prolonged stability allows the interval to be lengthened, especially below 45 mm [5, 21]. Patients with a normally functioning BAV and no valve degeneration at diagnosis are at low risk and may have episodic follow-up [69].

11.3. Prognosis after treatment

Elective proximal aortic surgery has an early mortality of 0.25–2%, and valve-sparing techniques keep at least 90% of patients free from valve reoperation 10–15 years later in a series not specific to BAV [5, 7]. In simple coarctation, surgical risk is below 1%, but increases after 30–40 years of age [4]. Repair of bicuspid AR combined with root remodelling has a cumulative incidence of reoperation of 20% at 15 years [1]. After TAVI in low-risk patients with bicuspid stenosis, mortality or disabling stroke was 4.1% at 3 years in the Evolut Low Risk Bicuspid Study, and in a matched series of balloon-expandable TAVI 5-year mortality was 13.2% in BAV and 13.7% in the tricuspid valve; long-term durability in young patients is not known, and device labelling asks that age be weighed for that reason [31–33, 102, 109]. In patients aged 60 years or more, the meta-analysis of reconstructed data showed a composite of death, stroke or rehospitalisation more frequent with TAVI than with surgery from 6 months onwards (HR 1.62 at 48 months), and the matched European study showed more stroke and valve dysfunction at 2 years with TAVI [107, 108].

12. Summary and Final Considerations

BAV is the most common congenital heart defect, with a prevalence of 0.5–2% according to guidelines and of 0.77% in an echocardiographic screening of newborns, and a male predominance of 2–3:1 [21, 22]. The 2021 international consensus describes it as a valvulo-aortopathy and classifies it into fused, 2-sinus and partial-fusion BAV, with ascending, root and extended aortic phenotypes, and with three clinical-prognostic groups: complex, typical and undiagnosed [1]. Heritability is high, but the genetic architecture is mainly polygenic: NOTCH1, SMAD6, ROBO4, GATA4, GATA5, GATA6, MAT2A and ADAMTS19 explain a small fraction of cases, larger in familial and early-onset forms than in sporadic ones, and 36 genome-wide association loci were identified in 2026 [10, 45, 46, 51]. In ClinGen, NOTCH1 has definitive validity for a spectrum that includes BAV, Adams-Oliver syndrome and thoracic aneurysm, SMAD6 is definitive and ROBO4 moderate [6, 17, 18].

The natural history combines frequent valvular dysfunction (valve surgery in about two thirds over a lifetime), slowly growing aortic dilatation, endocarditis (6% over a lifetime) and rare dissection (1.6% over a lifetime, about 3 per 10,000 patient-years), with preserved life expectancy in the typical form and survival of unrepaired BAV similar to that of the general population in a 2025 meta-analysis [26, 27, 66]. TTE is the central examination, complemented by CT or MRI, and surveillance is lifelong, including after valve replacement [5, 21]. No drug modifies the aortopathy; trials with atorvastatin, atenolol, telmisartan and losartan were negative or inconclusive, and medical treatment is limited to blood pressure control [94, 95]. Prophylactic aortic surgery follows thresholds of 55 mm, 50–52 mm with the root phenotype or risk factors and 45 mm with concomitant valve surgery, with divergences between European and North American guidelines; surgery remains the primary treatment of bicuspid stenosis, and TAVI an alternative in selected patients, with FDA labelling without a precaution against BAV since 2018–2020 but with limited data at low risk, and 2026 observational studies with signals of more late events than with surgery in patients aged 60 years or more [5, 21, 30, 32, 107, 108].

Echocardiographic screening of first-degree relatives, in whom BAV is found in about 7% and aortic dilatation in about 9%, is recommended by all guidelines [5, 25, 31]. Genetic testing is not indicated in isolated BAV and is reserved for forms with suspected HTAD, syndromic features, a family history of aortic disease, the root phenotype or early onset; a negative result does not exclude familial risk, and cascade testing requires a pathogenic or likely pathogenic variant [5, 7, 21]. The main gaps are the absence of prevalence estimates for Portugal and Brazil in the sources consulted (there is a Portuguese meta-analysis and a Brazilian TAVI registry), the scarcity of non-European data, and the lack of randomised trials of medical therapy with clinical outcomes and of TAVI trials dedicated to BAV, which are currently under way [10, 22, 110, 111, 123].

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87. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 142–143 (Au-Kline syndrome).
88. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 420–421 (Tricho-rhino-phalangeal syndrome type I).
89. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 400–401 (Lenz microphthalmia syndrome).
90. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 8–13 (Trisomy 18 syndrome).
91. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 14–17 (Trisomy 13 syndrome).
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