Genetics of bicuspid aortic valve: ready for clinical use?

Abstract

Several mechanisms have been described to explain the aetiology of bicuspid aortic valve disease (BAV). On the one hand, haemodynamic factors by which an altered flow through the valve induces an abnormal cusp formation, and on the other, genetic factors given the presence of familial cases (6.4% of firstdegree relatives) and its association with other left ventricular outflow tract (LVOT) abnormalities. Although most BAV cases are sporadic, an autosomal dominant pattern of inheritance with an incomplete penetrance has been proposed with an estimated heritability between 47% and 89%. It is more prevalent in men (9.2% vs 3.5%, respectively), which suggests that the loss of genes on the X chromosome may predispose its condition, however, these genes have not been yet identified. NOTCH1 has become the first gene associated with both familial and sporadic BAV and associated with other leftsided and rightsided congenital heart defects (such as tetralogy of Fallot, truncus arteriosus or hypoplastic left heart syndrome (HLHS)). This gene is highly expressed in the LVOT mesenchyme and endocardium at the location of the nascent valve cusps and the presence of haploinsufficiency has been associated with BAV and thoracic aortic aneurysms (TAA). Due to the common embryologic origin of the aortic valve, LVOT and proximal aorta, BAV frequently coexists with other leftsided congenital heart lesions, such as coarctation (CoA), Shone complex and HLHS. It has been reported that 50%–85% of patients with CoAassociated BAV. The highest penetrance of BAV in a genetic syndrome occurs in women with Turner syndrome, which is caused by a partial or complete absence of one X chromosome. BAV appears in >30% of patients, and the prevalence of associated CoA, aortic aneurysms and acute aortic dissections exceeds that in sporadic BAV cases. However, NOTCH1 variants explain only a small proportion of familial (2%) and sporadic (0.06%–0.08%) BAV disease suggesting incomplete penetrance. The nitric oxide synthase (NOS) pathway has also been shown to be relevant in the development of the tricuspid aortic valve. Nitric oxide has an important role in the aortic postdevelopment remodelling, angiogenesis and BAV (especially the right noncoronary cusp fusion morphotype). In this regard, mutations in the NKX2.5 gene, which encodes a protein related to nitric oxide promoters’ activation, have been identified in BAV families. Also, rare genetic variants in the GATA5 gene (related to transcription factors associated with cardiac morphogenesis) have been documented in several patients with BAV, suggesting a possible role for GATA5 in BAV pathogenesis. Several other genes have been reported to be associated with BAV in clinical studies but some of these associations may result from a coexisting disease. Recently, targeted sequencing of the coding regions of nine genes previously associated with BAV (NOTCH1, AXIN1, EGFR, ENG, GATA5, NKX25, NOS3, PDIA2 and TGFBR2) have not been associated with BAV in a casecontrol population. In this study, an intronic polymorphism (rs17290301) in the epidermal growth factor receptor gene and sexspecific genetic variants were the only genetic anomalies significantly associated with BAV. Additionally, deleterious variants of GATA4, NOTCH1, SMAD6 or ROBO4 are more common in patients with BAV with early onset of complications (such as aortic dissection or need of surgery for valvular disease) but not in BAV with heritable thoracic aortic disease. Finally, other common genetic variants, such as polymorphisms in the ACE or the metalloproteinase matrix, may act as modifiers of the pathogenesis of BAVassociated aortopathy, thus contributing to the variability of different clinical phenotypes. BAV can also represent a characteristic in patients with connective tissue disorders such as Marfan (FBN1 mutations) or LoeysDietz syndrome (TGFβR1 mutations) or nonsyndromic aortic diseases such as ACTA2 mutations. Whether the presence of BAV further influences the risk of aorticrelated events in syndromic and nonsyndromic familial TAA has not been systematically examined. Although some authors consider that the presence of BAV does not increase the aortic growth rate of patients with genetic aortopathy, others, however, have demonstrated the need for surgery at a younger age suggesting a less favourable natural history in this population. Despite strong evidence for a genetic basis for BAV, the genetic origins remain largely unknown. Therefore, to identify the genetic variants underlying BAV in recent years, wholeexome sequencing (WES) has been introduced in cases of family aggregation, however, a recent study using WES failed to identify high effect coding sense variants in multiple individuals with BAV. This analysis in distant relatives from a large family with an autosomal dominant inheritance of TAA identified a rare variant in the MAT2A gene (which encodes methionine adenosyltransferase II alpha), however, further studies are needed to demonstrate the potential mechanisms by which this abnormality is associated with aortic diseases. This suggests that targeted nextgeneration sequencing of a carefully selected part of the genome produces a more manageable data set compared with broader approaches, making analysis easier and faster. Based on a genomewide single nucleotide polymorphism array, a very recent study identified 47 recurrent copy number variations (CNVs) in patients with BAV and with TAA which were absent or extremely rare in controls. These findings suggest that rare CNVs may disrupt the expression of cardiac or vascular developmental genes in these regions, further highlighting the genetic heterogeneity of BAV and the multiple disease mechanisms leading to aortopathy. Also, recent data revealed that some epigenetic alterations, such as changes in DNA methylation and histone modification or regulation through microRNA (miRNA) may contribute to the cause and/or pathogenesis of the malformation through deregulation of the expression of genes that are relevant for heart development. The decreases of specific miRNA are associated with BAV and, also, associated with aortopathy. In order to delve into the implications of pathogenic NOTCH1 variants in the pathophysiology of BAV, Debiec et al evaluated the incidence of familial and sporadic cases of BAV associated with this gene and their association with congenital cardiac lesions. Also, they reviewed recent publications to provide an overview of Department of Cardiology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en RedCV, CIBER CV, Madrid, Spain