Genetic Insights into Bicuspid Aortic Valve Formation

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the population. It is generally diagnosed late in adulthood when deterioration of the abnormal leaflet becomes clinically evident. BAV patients have an increased risk of developing serious complications, including stenosis, regurgitation, endocarditis, dilation of the aorta, aortic dissection, and aneurysm. BAV is a heritable trait, but the genetic basis underlying this cardiac malformation remains poorly understood. In the last decade, thanks to studies in animal models as well as genetic and biochemical approaches, a large number of genes that play important roles in heart development have been identified. These discoveries provided valuable insight into cardiac morphogenesis and uncovered congenital-heart-disease-causing genes. This paper will summarize the current knowledge of valve morphogenesis as well as our current understanding of the genetic pathways involved in BAV formation. The impact of these advances on human health including diagnosis of BAV and prevention of cardiovascular complications in individuals with BAV or with a family history of BAV is also discussed.

Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity

“…Moreover, BAV has been observed in case reports of monozygotic twins (28). However, the male predominance and the association of BAV with Turner syndrome point to a possible X-linked inheritance (29).…”

“…Screening of first-degree family members of BAV patients is recommended by the consensus guidelines, due to its relatively high heritability rates (30), with the potential to identify a 9% unknown BAV in these firstdegree relatives (29). Moreover, is should be reminded that BAV first-degree relatives, even with normal tricuspid aortic valves, may develop artic dilatation (25).…”

A Roadmap to Investigate the Genetic Basis of Bicuspid Aortic Valve and its Complications

“…Despite significant limitations in BAV animal models, targeted gene deletions in mice, zebrafish, and cultured aortic valve interstitial cells have provided useful insights into candidate gene involvement in LVOT or aortic valve development (3,51,52). Some of these methods can be developed into high-throughput assays to screen candidate genes for roles in BAV formation or disease progression.…”

“…Despite years of investigation, researchers have yet to define genetic determinants of BAV and its complications, although most patients with BAV will develop complications requiring treatment. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without evidence of inheritance (3). …”

A novel nonsense mutation in NPHS1: is aortic stenosis associated with congenital nephropathy?

“…However, our results do point out to a potential role for NPHS1 in aortic stenosis, a specific form of congenital heart disease, that could manifest either shortly after birth or during adulthood. Nearly one per cent of the population is born with aortic stenosis, which can be very mild and thus would not appear in childhood, or very severe, and necessitates surgery just after birth (Garg 2006;Laforest and Nemer 2012). The underlying genetic and molecular pathways that lead to the narrowing and malformation of this valve are however, still, poorly understood.…”