Risk Factors for Aortic Valve Disease in Bicuspid Aortic Valve: A Family-Based Study

Division of Cardiology, Cincinnati Children's Hospital Medical Center, Ohio 45229-3039, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 05/2011; 155A(5):1015-20. DOI: 10.1002/ajmg.a.33974
Source: PubMed


Bicuspid aortic valve (BAV) is the most common cardiovascular malformation and is a risk factor for aortic valve disease (AVD). AVD typically manifests later in life, and the majority of cases have BAV. The purpose of this study was to identify risk factors for AVD in individuals with BAV. Families enriched for BAV were identified in a pediatric population, and echocardiography was performed on all family members. AVD was identified as stenosis and/or insufficiency, and BAV morphology was defined as right-left (RL), right-non (RN) or indeterminate. Heritability (h(2)) of AVD and BAV morphology was estimated using variance components analysis (SOLAR). To assess AVD risk over time, we used Generalized Estimating Equations methodology (SAS) adjusting for age and gender. A total of 1,128 individuals from 226 families were evaluated. BAV was identified in 281 individuals (25%), and AVD was identified in 167 (59%) individuals with BAV. Previously, we identified a high heritability for BAV (h(2)  = 0.89 ± 0.06, P < 0.00001), but the heritability of AVD in the present study (0.07 ± 0.17, P = 0.33) was low. AVD was significantly associated with BAV morphology (P = 0.0027) and age (P = 0.0068). Children with RN BAV and adults with RL BAV were more likely to develop AVD. BAV is determined largely by genetic effects, but the phenotypic variability of AVD is primarily determined by nongenetic factors. BAV morphology may have predictive value for the time course of AVD.

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Available from: Lisa J Martin, Sep 18, 2014
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    • "Rare, non-synonymous exonic variants in GATA5 have not been shown to correlate with cusp fusion [8,13]. Investigations of familial BAV in large cohorts have demonstrated that cusp fusion morphologies were inherited interchangeably within families [23,24]. Taken together, these studies suggest that differing BAV phenotypes may derive from a common genetic pathway influenced by downstream modifying elements. "
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    ABSTRACT: Background Bicuspid aortic valve (BAV) is the most common type of congenital heart disease with a population prevalence of 1-2%. While BAV is known to be highly heritable, mutations in single genes (such as GATA5 and NOTCH1) have been reported in few human BAV cases. Traditional gene sequencing methods are time and labor intensive, while next-generation high throughput sequencing remains costly for large patient cohorts and requires extensive bioinformatics processing. Here we describe an approach to targeted multi-gene sequencing with combinatorial pooling of samples from BAV patients. Methods We studied a previously described cohort of 78 unrelated subjects with echocardiogram-identified BAV. Subjects were identified as having isolated BAV or BAV associated with coarctation of aorta (BAV-CoA). BAV cusp fusion morphology was defined as right-left cusp fusion, right non-coronary cusp fusion, or left non-coronary cusp fusion. Samples were combined into 19 pools using a uniquely overlapping combinatorial design; a given mutation could be attributed to a single individual on the basis of which pools contained the mutation. A custom gene capture of 97 candidate genes was sequenced on the Illumina HiSeq 2000. Multistep bioinformatics processing was performed for base calling, variant identification, and in-silico analysis of putative disease-causing variants. Results Targeted capture identified 42 rare, non-synonymous, exonic variants involving 35 of the 97 candidate genes. Among these variants, in-silico analysis classified 33 of these variants as putative disease-causing changes. Sanger sequencing confirmed thirty-one of these variants, found among 16 individuals. There were no significant differences in variant burden among BAV fusion phenotypes or isolated BAV versus BAV-CoA. Pathway analysis suggests a role for the WNT signaling pathway in human BAV. Conclusion We successfully developed a pooling and targeted capture strategy that enabled rapid and cost effective next generation sequencing of target genes in a large patient cohort. This approach identified a large number of putative disease-causing variants in a cohort of patients with BAV, including variants in 26 genes not previously associated with human BAV. The data suggest that BAV heritability is complex and polygenic. Our pooling approach saved over $39,350 compared to an unpooled, targeted capture sequencing strategy.
    Full-text · Article · Sep 2014 · BMC Medical Genomics
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    • "The causes and mechanisms that give rise to aortic dilatation are not clearly understood, and it appears that genetic and hemodynamic factors coexist. On the basis that BAV and aortic dilatation could be manifestations of a single gene defect, some data would support a genetic component, as BAV has some patterns of inheritance 22 and links to other genetic diseases, such as Turner syndrome 23. Some pathways have been proposed, as mutations have been found in genes related to signaling and the transcriptional regulators (NOTCH1) 24, 25, although the knowledge about the genetic link between BAV and aortic dilatation is currently scant. "
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    ABSTRACT: Background and Aim: Bicuspid aortic valve (BAV) increases the risk of aortic valve dysfunction and ascending aorta aneurysm and, consequently, the need for aortic valve replacement and/or aortic repair. However, there is no universal consensus about the surgical criteria and the predictors for surgery. The aim of this study was to investigate related factors to the need for surgery in the setting of a strict long-term follow-up with relatively conservative surgical criteria. Methods: We prospectively followed 120 patients after the diagnosis of BAV. Predisposing factors for a future need for aortic valve replacement and ascending aorta repair were assessed. Aortic surgery was indicated when the ascending aorta diameter was ≥55 mm and was recommended based on patient characteristics and in the presence of a severe aortic valve dysfunction with an aortic diameter ≥50 mm. Results: During follow-up (mean, 86 months), 34 patients (28%) (mean age, 56±12 years) were surgically treated. Aortic valve dysfunction (n=22; 64%) and ascending aorta dilatation (n=12; 36%) were the indications for surgery. Aortic regurgitation was the most frequent valve dysfunction at the time of diagnosis for BAV, but aortic stenosis was the most frequent indication for surgery. The presence at surgery of either aortic regurgitation or stenosis was clearly related to age, with regurgitation predominating in patients under 55 years, and aortic stenosis in older patients. Multivariate Cox analysis showed that aortic stenosis (hazard ratio 4.1, p=0.001), indexed ascending aorta dilatation (hazard ratio 3.0, p=0.03) and left ventricular end-diastolic diameter ≥60 mm (hazard ratio=4.0, p=0.01) at diagnosis were factors associated with future surgery. Aortic dissection was not observed in patients that did not undergo surgery. Conclusions: A relatively conservative approach for the indication of ascending aortic surgery in BAV is safe. In this setting, the presence of aortic or left ventricle dilatation and aortic stenosis at diagnosis of BAV were predictive of the need for surgery in the follow-up.
    Full-text · Article · Jan 2013 · International journal of medical sciences
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    • "Exploring AVD in a pediatric population allows for examination of the disease process free from the confounding effects of cardiovascular comorbidities. Risk factors for AVD in children are poorly understood [13], but recently Calloway et al. reported that children with RN BAV and adults with RL BAV were more likely to develop AVD [14], suggesting BAV morphology may have predictive value for the time course of AVD. "
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    ABSTRACT: Bicuspid aortic valve (BAV) and thoracic aortic aneurysm (TAA) are two discrete cardiovascular phenotypes characterized by latent progressive disease states. There is a clear association between BAV and TAA; however the nature and extent of this relationship is unclear. There are both distinct and overlapping developmental pathways that have been established to contribute to the formation of the aortic valve and the aortic root, and the mature anatomy of these different tissue types is intimately intertwined. Likewise, human genetics studies have established apparently separate and common contributions to these clinical phenotypes, suggesting complex inheritance and a shared genetic basis and translating 3 patient populations, namely, BAV, TAA, or both, into a common but diverse etiology. A better understanding of the BAV-TAA association will provide an opportunity to leverage molecular information to modify clinical care through more sophisticated diagnostic testing, improved counseling, and ultimately new pharmacologic therapies.
    Full-text · Article · Aug 2012 · Cardiology Research and Practice
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