Genetic Basis of Familial Valvular Heart Disease

Abstract

HomeCirculation: Cardiovascular GeneticsVol. 5, No. 5Genetic Basis of Familial Valvular Heart Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBGenetic Basis of Familial Valvular Heart Disease Ratnasari Padang, MBBS, FRACP, Richard D. Bagnall, PhD and Christopher Semsarian, MBBS, FRACP, PhD Ratnasari PadangRatnasari Padang From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia (R.P., R.D.B., C.S.); Sydney Medical School, University of Sydney, Sydney, Australia (R.P., C.S.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (R.P., C.S.). Search for more papers by this author , Richard D. BagnallRichard D. Bagnall From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia (R.P., R.D.B., C.S.); Sydney Medical School, University of Sydney, Sydney, Australia (R.P., C.S.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (R.P., C.S.). Search for more papers by this author and Christopher SemsarianChristopher Semsarian From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia (R.P., R.D.B., C.S.); Sydney Medical School, University of Sydney, Sydney, Australia (R.P., C.S.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (R.P., C.S.). Search for more papers by this author Originally published1 Oct 2012https://doi.org/10.1161/CIRCGENETICS.112.962894Circulation: Cardiovascular Genetics. 2012;5:569–580IntroductionValvular heart disease (VHD) is a major cause of morbidity and premature death from cardiovascular diseases, making it an important clinical entity. Despite a dramatic decline in the incidence of rheumatic heart disease in industrialized countries, VHD remains highly prevalent. Although many VHDs are acquired during adult life, familial clustering and heritability have been noted for common heart valve defects, such as bicuspid aortic valve and myxomatous mitral valve prolapse, denoting an underlying genetic basis. Over the past decade, advances in our understanding of the genetic basis of familial VHD have been made through the unraveling of gene network and molecular mechanisms regulating normal valve development. Important progress has also arisen from a series of elegant studies that have focused on linkage analyses of large families with VHD, transgenic animal models, in vitro studies, and, more recently, microRNA and transcriptomic assessment of diseased tissues. Identification of the genes and molecular pathways responsible for the development of VHD has important implications in terms of improving current therapeutic strategies, as well as guiding the management of at-risk family members, with the ultimate aim to reduce the health burden of VHD. This article will summarize the current state of knowledge regarding the genetic basis of 2 common familial VHDs, namely mitral valve prolapse and bicuspid aortic valve, and highlight some of the recent findings that shed light on the pathogenesis of these diseases.Valvular heart disease (VHD) is a major cause of disability, diminished quality of life, and premature death from cardiovascular disease,1 making it an important clinical entity. Despite a dramatic decline in the incidence of rheumatic heart disease in industrialized countries, VHD remains highly prevalent.2 Although many VHDs are acquired during adult life, congenital forms present with abnormal valve structures at birth, yet may not manifest as valvular dysfunction and disease until later in life.3,4 Furthermore, familial clustering and heritability have been noted for common heart valve defects, such as bicuspid aortic valve (BAV) and myxomatous mitral valve prolapse (MVP), implying an underlying genetic basis.3,5,6 These familial VHDs can occur in isolation (nonsyndromic) or present as part of a clinical genetic syndrome, such as Marfan, Turner, and Noonan syndromes.7Traditionally, well-characterized multigeneration families have been invaluable for determining the genetic basis of disease, because they are amenable to marker-based genome-wide linkage analysis. However, the identification of causal genes in VHD has been hampered by complex genetic and phenotypic heterogeneity, incomplete penetrance, and the likely contribution of genetic modifier loci. Although in vitro studies and transgenic animal models that recapitulate the human phenotype have provided insights into the genetic basis of VHD, these findings do not always translate to humans. Therefore, concurrent studies on the molecular pathways regulating valvulogenesis have sought to highlight gene networks relevant to VHD.This review article will focus primarily on the 2 most common isolated VHDs, ie, MVP and BAV. The review will summarize the current knowledge regarding the genetic basis of MVP and BAV and highlight some of the recent findings that shed light on the pathogenesis of these diseases. Although there is much more to discover about the genetic causes of VHD, it is timely to review the current state of knowledge in these important cardiovascular genetic disorders.Overview of Development of Cardiac ValvesA key aspect of cardiac development is the formation and function of the cardiac valves. Cardiac valve development begins immediately after cardiac looping, at embryonic days 31 to 35 in humans, with the formation of endocardial cushions in the atrioventricular canal and outflow tract.8,9 Normal uridine diphosphate glucose dehydrogenase gene activity to synthesize glycosaminoglycan is critical for the early cell signaling events that establish the boundaries of these cushion-forming regions.10 Cardiac cushion formation involves the transformation of a subset of endothelial cells into mesenchymal cells in the cushion-forming area, which is induced by bone morphogenetic protein-2 (BMP-2) signals derived from adjacent myocardial cells.8 The mesenchymal progenitor cells migrate into the intervening cardiac jelly and proliferate to form swellings of valve primordial, which eventually give rise to valvuloseptal structures and adult valvular interstitial cells.8,11–13 The atrioventricular cushions contribute to atrioventricular (mitral and tricuspid) valve leaflets, whereas the outflow tract cushions contribute to semilunar (aortic and pulmonary) valve leaflets.3,8 The development of the outflow tract and semilunar valve is complex and involves coordinated interactions between the endocardial-derived mesenchyme, cardiac, and smooth muscle progenitors from the anterior or secondary heart field and the cardiac neural crest.14 Whereas the secondary heart field progenitor cells contribute to the outflow tract myocardium, a population of neural crest-derived cells migrate into the distal (truncal) part of the outflow tract cushions, which subsequently divide the outflow tract into aortic and pulmonary trunks, and differentiate into the vascular smooth muscle layer of the aortic arch.9,14, 15 A number of signaling pathways including Wnt/β-catenin, NOTCH, transforming growth factor β receptor (TGF-β), BMP, vascular endothelial growth factor, NFATc1 and MAPK, and transcription factors, including Twist1, Tbx20, Msx1/2, and Sox9, are active during this early stage of valvulogenesis. These pathways are collectively important in the regulation of cell migration, proliferation, and extracellular matrix expression in the developing valves.8,13,16,17Later in embryonic valve development, cell proliferation decreases and the fused endocardial cushions remodel and thin out to form mature valve leaflets, which are characterized by increasing complexity and organization of the extracellular matrix, and compartmentalization of valvular interstitial cells.8,13 The molecular pathway that regulates this later stage of valvulogenesis is less well understood, but it involves periostin, a component of the extracellular matrix protein.18 The periostin gene has been identified as a molecular switch that promotes the differentiation of endocardial cushion cells into a fibroblastic cell lineage, rather than into myocardial or osteochondral cell lines, and regulates cushion remodeling, separation of the developing atrioventricular valve from the underlying myocardium, and its transformation into mature valve leaflet and the supporting apparatus.9,18 The mature valve leaflets are stratified into 3 layers with distinct mechanical properties arranged in orientation to the blood flow: a flexible, elastin-rich atrialis/ventricularis layer, a central shock-absorbing proteoglycan-rich spongiosa layer, and a tensile, collagen-rich fibrosa layer.19 The process of valve compartmentalization and remodeling occurs at late gestation and continues into postnatal life, suggesting that mechanisms of prenatal valve development persist during postnatal valve growth and maintenance.6,11 Furthermore, evidence suggests that developmental signaling pathways are shared between heart valves and the precursors of cartilage, tendon, and bone, playing a critical role at this later stage of valve maturation/remodeling.19 These pathways include BMP-2–mediated induction of Sox9 and aggrecan, receptor activator of NFκB ligand–mediated induction of NFATc1, and FGF4-mediated induction of scleraxis and tenascin.17,19,20Cardiac valve development during embryogenesis is therefore complex, with an integrated mechanism of genetic factors, activation of signaling pathways, as well as external environmental factors, such as the physical forces of blood flow. Because many of the signaling pathways and transcription factors responsible for valve development are reactivated in pediatric and adult valve diseases,3,21 the insights gained from understanding normal valvulogenesis have provided a platform to identify potential candidate genes involved in familial VHDs.Mitral Valve ProlapseClinical SignificanceMVP is a common disorder, which affects 2.4% of the general population and exhibits strong heritability.22–24 Because MVP is defined by the abnormal relationship of mitral leaflets to their surrounding structures, echocardiography has become a diagnostic standard to confirm its presence. In a pivotal 3D echocardiographic study in the late 1980s, Levine et al25 demonstrated that the mitral annulus was in fact saddle shaped, with the most superior aspects positioned anteriorly and posteriorly and the most inferior aspects positioned medially and laterally. This improved understanding of normal mitral valve anatomy has greatly enhanced the diagnostic specificity for MVP without loss of sensitivity.22 Because successful genetic studies rely on accurate phenotypic definition, the increased diagnostic specificity for MVP has been central in enabling the advances to be made in MVP genetics over the past few years.MVP is characterized by fibromyxomatous degeneration of the mitral valve, leading to progressive thickening and expansion of the leaflet(s) and lengthening of the chordae tendineae, which results in superior displacement of the leaflet(s) into the left atrium during systole.23,24,26 The clinical phenotype of MVP is widely heterogeneous,24,27,28 ranging from a benign clinical course with normal life expectancy to adverse outcomes with significant morbidity and mortality resulting from the development of valvular insufficiency. Although most patients are asymptomatic, up to 13% of affected subjects develop serious MVP-related complications,28 attributed to significant mitral regurgitation, congestive heart failure, infective endocarditis, arrhythmias, and, in worst cases, sudden cardiac death.22,23,27 MVP is the leading cause of isolated mitral regurgitation, requiring surgical intervention in developing nations.12,22,27Pathogenesis of MVPHistological examination of myxomatous MVP leaflets characteristically demonstrates activated interstitial myofibroblast-like cells, disorganized fragmentation of collagen and elastin fibers, and expansion of the spongiosa layer that have resulted from the accumulation of proteoglycans and glycosaminoglycans, which extend into the load-bearing fibrosa.22,29 This alteration of extracellular matrix synthesis and maladaptive remodeling by activated valvular interstitial cells result in a disruption in the mechanical integrity of the leaflet(s) which, together with normal wear and tear, leads to leaflet(s) stretching and expansion.12Although the pathological features of MVP are well known, the precise cellular and molecular mechanisms that contribute to the development of MVP are less clear. Isolated MVP is absent in newborn babies,30 suggesting that it may develop from a combination of genetic variation with age-dependent penetrance, postnatal disruption of cellular signaling, and environmental factors, including repetitive mechanical stress from normal physiological wear and tear (Figure 1).27,31 It is postulated that hemodynamic shear stress and impact-induced damage to the superficial lining layer of valvular endothelial cells leads to the release of proinflammatory cytokines, such as TGF-β and vasoactive substance; eg, endothelin-1 and prostanoids.11,32–35 This then activates the residing valvular interstitial cells, which transform into myofibroblast-like cells and secrete excessive levels of catabolic enzymes, including the collagenases MMP-1 and MMP-13, the gelatinases MMP-2 and MMP-9, cysteine proteases cathepsin C and M, and interleukin-1β, a cytokine that induces the secretion of proteolytic enzymes.34 Moreover, a proportion of valvular interstitial cells transform toward a hyperplastic CD34+ fibrocyte phenotype, which synthesizes MMP-9 and collagen-III, and seem to take part in leaflet remodeling (Figure 2).31,36 Together, these changes alter the metabolism and composition of the extracellular matrix and, although most pronounced in the spongiosa layer, also affect the fibrosa backbone layer, hence compromising the leaflet structural integrity and biomechanics. Ultimately, remodeling of the extracellular matrix and excessive glycosaminoglycan and water accumulation, give the diseased leaflets their classical myxomatous appearance.22Download figureDownload PowerPointFigure 1. Factors contributing to MVP development and progression. MVP indicates mitral valve prolapse; BP, blood pressure; Fbn, fibrillin; and MMP, matrix metalloproteinases.Download figureDownload PowerPointFigure 2. Schematic representation of postulated pathogenesis of mitral valve prolapse (MVP). MVP is believed to be the consequence of a maladaptive response of a genetically predisposed mitral valve to repetitive mechanical stress. As well as having a possible direct effect of shear stress on the residing valvular interstitial cells (VICs), this impact-induced damage to the superficial lining layer of valvular endothelial cells (VEC) leads to the release of proinflammatory cytokines and vasoactive substances. This, in turn, stimulates transformation of VICs to an active myofibroblast-like cells. The activated VICs then secrete excessive levels of catabolic enzymes, which result in collagen degradation, deposition of proteoglycans, extracellular matrix (ECM) disarray and remodeling, ultimately leading to disruption in the mechanical integrity of the leaflet and leaflet prolapse. MMP indicates matrix metalloproteinases; BMP, bone morphogenetic protein; TGF-β, transforming growth factor type β.Genetic Basis of MVPMVP can be sporadic, familial, or occur in the context of a syndrome, the latter occurring as part of heritable connective tissue disorders, which are often attributed to specific mutations in extracellular matrix genes. A summary of the genetic factors in MVP is provided in Table 1.Table 1. Summary of Gene Anomalies and Polymorphisms Associated With the Development of Mitral Valve ProlapseStudy CohortsGenetic Anomalies and Polymorphisms Associated With MVP DevelopmentReferenceAnimal studyMiceFBN1-deficient mouse model32Cardiac-specific MMP-2 transgenic mouse model54Adamts9 haploinsufficient mice53Cavalier King Charles SpanielsLocus on CFA13 and CFA1492Human studyFamilial MVPFamilies with idiopathic autosomal dominant pattern of inheritance for MVPLocus on Chr 16p11.2-p12.1 (MMVP1)45Locus on Chr 11p15.4 (MMVP 2)46Locus on Chr 13q31.3-q31.2 (MMVP3)42Families with X-linked form of MVP (myxomatous valvular dystrophy)Filamin A gene mutation (Chr Xq28)43, 44Sporadic MVPChinese Han population cohort living in TaiwanPLAU gene T4065C polymorphisms48Collagen IIIα1 exon 31 G2209A polymorphisms, particularly with GG genotype47, 93FBN1 exon 15 TT and exon 27 GG polymorphisms51Angiotensinogen gene M235T polymorphisms, particularly with TT genotype and T alleleACE-I gene (Chr 17q23) insertion /deletion polymorphisms affecting intron 1650White populationAngiotensin II type 1 receptor gene A1166C polymorphism, particularly with C allele52Pediatric cohort in TurkeyFBN1 56GC intronic polymorphism94Syndromic MVPMarfan syndromeFBN1 (Chr 15q21.1) and TGFβR2 (Chr 3p24.2-p25) mutations3, 26Loeys–Dietz syndromeTGFβR1 and TGFβR2 mutationsEhler–Danlos syndromeCollagen type I, III, V, XI, and tenascin mutationsStickler syndromeCollagen type II and XI mutationsWilliams–Beuren syndromeElastin gene mutationOsteogenesis imperfecta,Collagen type I mutationPseudoxanthoma elasticumATP-binding cassette protein ABCC6 mutationMVP indicates mitral valve prolapse; FBN, fibrillin; MMP, matrix metalloproteinases; CFA, canine chromosome; MMVP, myxomatous mitral valve prolapse; Chr, chromosome; PLAU, urokinase–plasminogen activator; ACE-I, angiotensin-converting enzyme inhibitor; and TGFβR, transforming growth factor β receptor.Mutations in fibrillin-1 (FBN-1) and, less commonly, in TGF-β receptor-2 (TGFBR2), cause Marfan syndrome Type I and Type II, respectively, in which MVP is common. Advances in understanding MVP pathogenesis have been made using an FBN1-deficient mouse model that recapitulates human Marfan syndrome in a landmark study by Dietz and colleagues.32 Fibrillin-1 is a major structural component of the extracellular matrix microfibrils and a key regulator of TGF-β availability.37 TGF-β regulates extracellular matrix content and remodeling, as well as valvular interstitial cell differentiation and activity, via autocrine signaling.11,34,37,38 TGF-β isoforms are synthesized in the intracellular compartment as large precursors that are cleaved into mature TGF-β and its propeptide, called latency-associated peptide, which are covalently bound to form inactive small latent complexes.38 This complex remains intracellular until it is bound to latent TGF-β–binding protein, forming a large latent complex. Fibrillin-1 has been shown to bind to latent TGF-β–binding protein and the large latent complex, thus allowing fine control of TGF-β levels and activity by sequestering biologically active TGF-β into the extracellular matrix.37,38 Therefore, deficiency of fibrillin-1 results in increased TGF-β signaling within the extracellular matrix, as demonstrated by the increased levels of phosphorylated Smad2 and the expression of TGF-β–responsive extracellular matrix genes, such as Tgfbi, endothelin-1 (Edn1), and tissue inhibitor of metalloproteinase1 (Timp1).32 It is remarkable that TGF-β antagonism in vivo using neutralizing antibodies was able to rescue the valve phenotype of FBN1-deficient mice.32 Furthermore, Losartan, an angiotensin II type 1 receptor antagonist, prevents and possibly reverses the aortic root dilatation and MVP in mice with Marfan syndrome, probably by decreasing TGF-β–mediated ERK1/2 activation, a principal effector of disease in FBN1-deficient mice.37,39 These insightful findings suggest that myxomatous MVP may result from dysregulation of conserved signaling pathways and be amenable to therapeutic intervention. Although linkage between FBN1 and several of the collagen genes have not been demonstrated in autosomal dominant MVP,40,41 the established role of TGF-β in the pathogenesis of MVP in Marfan syndrome suggests that it may be relevant in nonsyndromic forms of MVP.12The contribution of genetic factors in nonsyndromic MVP is supported by family studies, which indicate genetic heterogeneity with autosomal dominant and X-linked modes of inheritance.22 Incomplete penetrance with age- and sex-dependent expressivity further contributes to the striking clinical heterogeneity even within the same family.22,24,27,42 X-linked myxomatous valvular dystrophy is a rare form of familial multivalvular myxomatous degeneration caused by mutations in the filamin A (FLNA) gene located on chromosome Xq28, in which MVP is a frequent manifestation.43,44FLNA encodes a large cytoskeletal actin-binding protein that directly coordinates the localization and activation of Smad proteins, especially Smad2, and serves as a positive regulator of TGF-β signaling.43 Although defective Smad signaling caused by FLNA mutation has not been shown, understanding the role of FLNA in modulating TGF-β signaling has provided another clue toward an improved understanding of myxomatous MVP pathogenesis. Furthermore, genome-wide linkage analyses in large families have mapped MVP loci to chromosomes 16p11.2-p12.1 (MMVP1),45 11p15.4 (MMVP2),46 and 13q31.3–31.2 (MMVP3),42 although the causative genes remain to be identified.In sporadic MVP, where family studies are not informative, associations with single-nucleotide polymorphisms in genes implicated in extracellular matrix remodeling, collagen metabolism, and the renin–angiotensin–aldosterone system (RAAS) have been examined (Table 1). The association of sporadic MVP with the G/G genotype of a polymorphism in exon 31 of the collagen IIIα1 gene (COL3A1)47 and 3 polymorphisms in the FBN1 gene have been reported.38,39 However, the generalizability of these results is restricted by the small number of patients, and is in contrast with the previously mentioned linkage analyses on several pedigrees that showed no linkage of these genes to autosomal dominant MVP. A polymorphism in the 3’ untranslated region of the urokinase–plasminogen activator gene, which plays a role in the pathogenesis of elastin and collagen degradation in arterial aneurysms, was also reportedly associated with MVP.48 It is interesting that in another study of MVP patients, an MMP-3 promoter haplotype-1612 5A/5A polymorphism was associated with severe mitral regurgitation and more pronounced left ventricular remodeling.49 It is speculated that the MMP-3 promoter 5A/5A polymorphism may result in increased MMP-3 expression in the myocardium, which then accentuates the adaptive response of the myocardium to the volume overload of mitral regurgitation and hence more adverse disease course.49 This suggests that genetic variation influences the disease course in MVP.A subset of MVP patients present with a variety of symptoms that seem to be independent from their underlying valve disease, including chest pain, dyspnea, dysrhythmia, anxiety, and syncope, and this is collectively termed MVP syndrome. The misperception that these symptoms frequently occur concomitantly with MVP has led to the practice of obtaining screening echocardiograms on patients with atypical or nonspecific cardiovascular symptoms.27 Thus, MVP syndrome may be overdiagnosed as a result of 2 common things occurring together, without necessarily bearing any pathophysiological relationship. It is interesting that perturbations in autonomic, neuroendocrine, and renin–angiotensin–aldosterone system regulation have been reported among symptomatic patients with MVP.31 A number of studies have subsequently demonstrated genetic association between MVP syndrome and the components of the renin–angiotensin–aldosterone system, namely an angiotensin I–converting enzyme insertion/deletion polymorphism in intron 16,50 the TT genotype of the angiotensinogen Met235Thr polymorphism,51 and the C allele of the angiotensin II type 1 receptor A1166C polymorphism,52 although these studies are limited by the relatively small cohort of patients with MVP syndrome. However, further studies of asymptomatic patients with MVP have failed to show evidence of abnormal autonomic or neuroendocrine function, either at rest or during tilt testing.27 Therefore, although abnormal autonomic function might be responsible for symptoms in some patients with MVP, it remains unclear whether their MVP is directly related or incidental.27Furthermore, studies in animal models have also highlighted genetic factors involved in MVP pathogenesis. Proteoglycan accumulation is a hallmark of MVP,34 and mice haploinsufficient for the versican-specific protease, Adamts9, display abnormal valve morphogenesis and subsequently develop myxomatous mitral valve leaflets during adulthood as a result of versican accumulation.53 In addition, enzymes that degrade the extracellular matrix, such as the gelatinase MMP-2, may mediate myxomatous degeneration of the mitral valve leaflet, and the cardiac-specific transgenic expression of MMP-2 in mice reproduces many of the pathological features of MVP.54Recently, gene expression microarray technology was used to gain a more unbiased, global view of the genetic signature of prolapsed mitral valve tissue from patients with idiopathic MVP, compared with control valve tissue from transplant donors. The study identified decreased expression of the metallothioneins 1 and 2 (MT1/2), which protect against oxidative stress, and ADAMTS-1, an abundant aggrecanase in the mitral valve leaflets that is implicated in proteoglycan degradation.55 Subsequent in vitro silencing of the expression of metallothioneins 1 and 2 in valvular interstitial cells culture resulted in the upregulation of TGF-β2 activity and TGF-β2 secretion, with consequent downregulation of ADAMTS-1, leading to versican accumulation and remodeling of the extracellular matrix, recapitulating the features of human MVP.55Collectively, these findings provide an insight into the genetic basis of MVP, which is complex, highly heterogeneous, and most likely involves causative gene mutations with genetic modifier loci that influence the disease course.Bicuspid Aortic ValveClinical SignificanceBAV occurs when the aortic valve has 2 cusps, rather than 3, and represents the most common form of congenital cardiac malformation, affecting ≈1.4% of the general population.56,57 BAV has a male predominance of ≈3:1,58 and at least 35% of those affected develop serious complications including aortic stenosis and regurgitation requiring valve replacement, endocarditis, ascending aortic aneurysm, and dissection.59 BAV underlies 70% to 85% of stenotic aortic valve in children and at least 50% of aortic stenosis in adults.12,60 Furthermore, BAV carries an 8-fold increased risk of aortic dissection, and over a 25-year period, the risk of valve replacement is 53%, aneurysm formation is 26%, and aortic surgery is 25%.56 As such, BAV represents a greater burden of disease than all other congenital heart diseases combined.58,61Disorders of aortic valvulogenesis tend to be regarded in the context of a phenotypic continuum, ranging from aortic valves with a single leaflet to those with 4 leaflets.59 Within this continuum, BAV exists and demonstrates a wide morphological variation, as seen in human cases of BAV (Figure 3) and observed in BAV of Syrian hamsters.62 BAV morphological phenotypes range from the typical form with 2 unequal-sized leaflets and the larger leaflet having a central raphe that has resulted from commissural fusion (ie, functionally bicuspid), to the less common form with 2 approximately symmetrical leaflets without a raphe (ie, anatomically bicuspid).58,63 Fusion of the right and left coronary cusps is the most common pattern of BAV and is associated with the coarctation of the aorta, whereas the fusion of the right and noncoronary cusps, the second commonest form, is associated with more cuspal pathology.58Download figureDownload PowerPointFigure 3. Different phenotypic spectrum of BAV morphology. A, Trileaflet aortic valve with complete fusion of the right and left (R-L) coronary cusps; B, Trileaflet aortic valve with complete fusion of the R-L coronary cusps and partial fusion of the right and noncoronary cusps; (C) and (D) Bileaflet aortic valve with extensive raphe in the fused leaflet; E, Bileaflet aortic valve with a vestigial raphe; F, True bicuspid aortic valve without raphe. Figures A and B are classified as functionally bicuspid and the remaining are classified as anatomically true bicuspid.Like MVP, BAV can occur sporadically as an isolated birth defect, can be familial, and can occur as part of a syndrome with more global clinical manifestations, such as Turner, Williams-Beuren, and Andersen syndromes. Furthermore, BAV is also recognized to coexist with other congenital cardiovascular malformations, most commonly with coarctation of the aorta, and with cardiac septal defects or the genetically related hypoplastic left heart syndrome.58,64 This suggests that BAV is not only a disorder of valvulogenesis, but it also represents a more complex coexistent genetic disease of the aorta and cardiac development.58,60Pathogenesis of BAVDespite its high prevalence, the pathogenesis of BAV is largely undetermined, although gene mutations leading to alterations in cell migration and signal transduction, in conjunction with nongenetic factors such as blood flow during valvulogenesis, may contribute to its formation prenatally.3 Because the relationship of the individual valve cusps to specific endocardial cushion progenitors is not known,8 BAV could result from a failure of separation of primordial cusps.3 Meanwhile, the pathogenesis of aortic valve dysfunction in BAV is thought to be the result of dysregulation in the complex molecular hierarchies controlling late valve developm