Bicuspid aortic valve is the most common congenital valvular heart anomaly in the general
population, with a prevalence estimated between 0.5 - 2%. It is more common in males than
females with ratios reported between 2:1 and 3:1. The prevalence of BAV shows significant
differences amongst different ethnic groups. BAV sometimes associates with other,
non-valvular cardiovascular phenotypes, e.g. aortic coarctation, left dominant coronary
artery system and intracranial aneurysms. Presence of BAV is strongly associated with
dilatation of the ascending aorta irrespective of valve function. BAV related dilatation of
the ascending aorta has been reported in 56% of those aged 30 years old and 88% of those aged
80 years old.
Presence of BAV can be associated with serious cardiovascular complications. In a long term
observational study, the overall survival of BAV patients was equal to age and sex matched
subjects from the general population, but BAV was associated with the need for surgical
intervention in 27% of subjects. Additionally, cardiovascular medical events (heart failure,
infective endocarditis and stroke) occurred in 33% of all subjects with BAV over that period.
BAV shows strong familial clustering, indicating that it has a strong genetic basis. In an
echocardiographic survey of first degree relatives of patients with BAV 36.7% of families had
at least 2 members with this anomaly. In a study of 309 subjects from 48 extended families
heritability of BAV was calculated at 89%.A whole genome linkage scan performed in 38
extended families (324 individuals), showed evidence for linkage with 5 chromosomal loci -
18q22, 5q21, 13q34, 9q34, 17q24. When analysed separately, the majority of families
contributed only to a single locus suggesting heterogenic genetic origin of BAV. Based on
these observation an oligogenic model of autosomal dominant inheritance with reduced
penetrance has been suggested.
Despite strong familial clustering, only few genetic loci have been associated with BAV so
far. The strongest evidence exist for association of BAV with NOTCH1 gene (translocation
associated protein) - the product of which is an important element in developmental control
of cell fate decisions. Other candidate loci include TGFBR2 (transforming growth factor beta
receptor 2 gene), GATA5 (GATA-binding protein gene) and eNOS (endothelial nitric oxide
synthase gene). However, the identified loci explain only small proportion of BAV
heritability.
Modern DNA analysis, notably next generation sequencing, allows variants associated with
disease to be identified more rapidly and with increased precision. The objective of this
project is to use such technology to identify genetic variants and genes predisposing to BAV
using a combination of case-control and family-based approaches. A better understanding of
the genetic underpinnings of BAV could in the future help to improve the management of this
valvular heart condition.
This BRAVE study will recruit patients with antecedent or new diagnosis of BAV. As many
relatives of the index patient as possible will be recruited to the study (family based
analysis). They will be screened with echocardiography for the presence of BAV. Additional
group of unrelated healthy individuals with three leaflet valves will be recruited for the
purpose of case control analysis.
Demographic and clinical data from all participants will be collected using purposefully
designed questionnaires and by accessing their medical records. Data on imaging
investigations will be obtained from the medical records or from the echocardiogram performed
for the purpose of screening.
Blood samples will be used for the purpose of isolation of genetic material and subsequent
genetic analysis. Additional laboratory tests may be performed on the blood samples to
provide supporting evidence to the results of genetic analysis.
The main analyses will consist of identifying and cataloguing genetic variants for each
individual from the DNA sequencing and then seeing whether any particular variant or sets of
variants are more commonly present in BAV subjects versus those without BAV (case-control
design) or present in subjects with BAV but not in unaffected family members (family-based
approach).