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).
