The importance of genetics and genetic counselors in the evaluation of patients with bicuspid aortic valve and aortopathy

Abstract

Purpose of reviewBicuspid aortic valve (BAV) is a common congenital heart defect, with an estimated frequency of 1-2% in the general population. BAV may occur as an isolated finding or as a feature of certain syndromes. This article discusses potential genetic causes of BAV, includes a list of current known and candidate genes associated with BAV, provides a hypothetical case demonstrating the importance of genetic testing and cascade screening, and highlights the value of genetic counselors specializing in cardiovascular genetics. Recent findingsIndividuals with BAV are at significantly increased risk of progressive aortic valve disease and aortic root aneurysms. There is high heritability associated with BAV, and several specific genes have recently been associated with BAV. There is wide phenotypic variability among BAV malformations, including which cusps are involved and the degree of aortic root involvement. Genotype-phenotype correlations exist that impact treatment recommendations. Genetic testing can reduce morbidity and mortality by guiding management strategies and identifying asymptomatic relatives before significant complications occur.

Evolving Surgical Approaches to Bicuspid Aortic Valve Associated Aortopathy

“…In the 1990 and 2000s, several observations led investigators to think that a strong genetic role contributed to bicuspid aortopathy and that the risk of acute aortic complications was substantially increased in this patient population (10). Although not universally seen in BAV patients, the NOTCH signaling pathway has been implicated in most studies as a genetic cause for BAV and bicuspid aortopathy (11, 12). As technology advances, our understanding of the genetic contributors to BAV and bicuspid aortopathy will improve.…”

Biomechanical properties and histomorphometric features of aortic tissue in patients with or without bicuspid aortic valve

“…The two main theories explaining the phenomenon of aortopathy in BAV disease are the genetic and the hemodynamic hypothesis (6). According to the genetic theory, the presence of aortic wall fragility is a consequence of a common developmental defect involving the aortic valve and the aortic wall and the mutation in NOTCH1 gene the main pathway involved (7)(8)(9)(10)(11). This hypothesis is further supported by reporting altered molecular and/or metabolic characteristics in the aortic wall and valve leaflets in BAV and differences in elastic lamellae, with a loose attachment of vascular smooth muscle cells (VSMCs), and precocious apoptosis.…”

Medial tunica degeneration of the ascending aortic wall is associated with specific microRNA changes in bicuspid aortic valve disease

“…On the other hand, evidence of familial clustering of BAV suggests that familial inherited BAV aligns with autosomal dominant transmission with reduced penetrance ( 6 ). Analysis of particular pedigrees, positional cloning approach, and genetic analysis have proven to be crucial to the discovery of multiple genetic loci associated with familial BAV, including the involvement of the Notch1 and GATA binding protein 5 ( 7 , 8 ) Different phenotypes of BAV have been identified according to cusp fusion ( 9 ): i) Phenotype I, right-left (R-L) coronary cusp fusion, which is associated with coarctation of the aorta, aortic stenosis and increased aortic wall shear stress; ii) phenotype II, right-non-coronary (R-NC) cusp fusion, associated with cusp pathology, aortic stenosis and regurgitation, aortic aneurysm, larger aortic arch dimensions and myxomatous mitral valve disease; and iii) phenotype III, left-non-coronary (L-NC) cusp fusion, which is rare.…”