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Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

ABSTRACT: Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

SUBMITTER: Luyckx I

PROVIDER: S-EPMC6777542 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

Luyckx Ilse I Kumar Ajay A AA Reyniers Edwin E Dekeyser Emily E Vanderstraeten Kathleen K Vandeweyer Geert G Wünnemann Florian F Preuss Christoph C Mazzella Jean-Michaël JM Goudot Guillaume G Messas Emmanuel E Albuisson Juliette J Jeunemaitre Xavier X Eriksson Per P Mohamed Salah A SA Kempers Marlies M Salemink Simone S Duijnhouwer Anthonie A Andelfinger Gregor G Dietz Harry C HC Verstraeten Aline A Van Laer Lut L Loeys Bart L BL

European journal of human genetics : EJHG 20190228 7

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. ...[more]

PMID: 30820038

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Project description:ImportanceThe prevalence and characteristics of bicuspid aortic valve (BAV) are mainly reported from selected cohorts. BAV is associated with aortopathy, but it is unclear if it represents a fetal developmental defect or is secondary to abnormal valve dynamics.ObjectiveTo determine the prevalence of BAV and BAV subtypes and to describe the associated aortopathy in a large, population-based cohort of newborns.Design, setting, and participantsThe Copenhagen Baby Heart Study was a cross-sectional, population-based study open to all newborns born in Copenhagen between April 1, 2016, and October 31, 2018. Newborns with BAV were matched 1:2 to newborns with a tricuspid aortic valve (non-BAV group) on sex, singleton/twin pregnancy, gestational age, weight, and age at time of examination.ExposuresTransthoracic echocardiography within 60 days after birth.Main outcomes and measuresPrimary outcome was BAV prevalence and types, ie, number of raphes and spatial orientation of raphes or cusps (no raphes), according to the classification system of Sievers and Schmidtke (classified as type 0, 1, or 2, with numbers indicating the number of raphes). Secondary outcome was valve function and BAV-associated aortopathy, defined as aortic diameter z score of 3 or greater or coarctation.ResultsIn total, 25 556 newborns (51.7% male; mean age, 12 [SD, 8] days) underwent echocardiography. BAV was diagnosed in 196 newborns (prevalence, 0.77% [95% CI, 0.67%-0.88%]), with male-female ratio 2.1:1. BAV was classified as type 0 in 17 newborns (8.7% [95% CI, 5.5%-13.5%]), type 1 in 178 (90.8% [95% CI, 86.0%-94.1%]) (147 [75.0% {95% CI, 68.5%-80.5%}] right-left coronary raphe, 27 [13.8% {95% CI, 9.6%-19.3%}] right coronary-noncoronary raphe, 4 [2.0% {95% CI, 0.8%-5.1%}] left coronary-noncoronary raphe), and type 2 in 1 (0.5% [95% CI, 0.1%-2.8%]). Aortic regurgitation was more prevalent in newborns with BAV (n = 29 [14.7%]) than in those without BAV (1.3%) (absolute % difference, 13.4% [95% CI, 7.8%-18.9%]; P < .001). Newborns with BAV had higher flow velocities across the valve (0.67 [95% CI, 0.65-0.69] m/s vs 0.61 [95% CI, 0.60-0.62] m/s; mean difference, 0.06 m/s [95% CI, 0-0.1]) and larger aortic root and tubular ascending aortic diameters than those without BAV (10.7 [95% CI, 10.7-10.9] mm vs 10.3 [95% CI, 10.2-10.4] mm; mean difference, 0.43 mm [95% CI, 0.2-0.6 mm] and 9.8 [95% CI, 9.6-10.0] mm vs 9.4 [95% CI, 9.3-9.5] mm; mean difference, 0.46 mm [95% CI, 0.30-0.70], respectively) (P < .001 for all). Aortopathy was seen in 65 newborns (33.2%) with BAV (62 with aortic z score ≥3; 3 with coarctation).Conclusions and relevanceAmong newborns in Copenhagen, the prevalence of BAV was 0.77%. Aortopathy was common in newborns with BAV, suggesting that it also represents a fetal malformation.

Project description:BackgroundAortic dissection is a life-threatening complication of bicuspid aortic valve (BAV)-associated aortopathy. In these populations, whilst prophylactic replacement of proximal thoracic aortic aneurysms (TAAs) is generally recommended at threshold diameters ≥5.5 cm, dissection may occur in smaller aortas. An alternative size-based parameter, the cross-sectional aortic area/patient height ratio (indexed aortic area, IAA), correlates with increased dissection risk at abnormal values > 10 cm2/m. We sought to assess the utility of the IAA in identifying at-risk BAV-associated TAAs with abnormal IAA, albeit with sub-threshold aortic diameter.Materials and methodsWe retrospectively identified 69 patients with BAV-associated TAAs who underwent surgical repair between 2010 and 2016. Aortic diameter was measured on pre-operative imaging, and IAA calculated, at the mid-sinus of Valsalva, sino-tubular junction and mid-ascending aorta for each patient. We determined proportions of aneurysms with IAA >10 cm2/m, median IAAs corresponding to aortic diameters <4.0 cm, 4.0-4.5 cm, 4.5-5.0 cm, 5.0-5.5 cm and >5.5 cm, and median aortic diameters corresponding to an abnormal IAA.Results50.9%, 12.5% and 64.6% of aneurysms at the sinus of Valsalva, sino-tubular junction and mid-ascending aorta, respectively, had an abnormal IAA. 51.9% and 88.9% of patients with aortic diameter 4.5-5.0 cm and 5.0-5.5 cm, respectively, had an abnormal IAA. In aneurysms with abnormal IAA involving the sinus of Valsalva, sino-tubular junction, and mid-ascending aorta, median aortic diameters were 4.98 cm, 5.04 cm and 5.11 cm, respectively. Overall, 57/72 (79.2%) at-risk aneurysms with IAA >10 cm2/m had diameters smaller than the 5.5 cm guideline cut-off for surgical intervention.ConclusionSignificant proportions of BAV-associated TAAs are at increased risk of aortic dissection attending an IAA >10 cm2/m, whilst not fulfilling the size criteria indicating aortic surgery in contemporary guidelines. Further analysis of IAA in larger BAV cohorts is necessary to clarify its role in patient selection and optimal timing for prophylactic aortic replacement.

Project description:OBJECTIVES:The objectives of this study were to investigate an association between the magnitude of flow-mediated aortic wall shear stress (WSS) and medial wall histopathology in patients with bicuspid aortic valve (BAV) with aortopathy. METHODS:Patients with BAV (n = 27; 52 ± 15 years; 3 women; proximal thoracic aorta diameter = 4.4 ± 0.7 and 4.6 ± 0.5 cm) who underwent prophylactic aortic resection received preoperative 3-dimensional time-resolved phase-contrast magnetic resonance imaging with 3-dimensional velocity encoding to quantify WSS relative to a population of healthy age- and sex-matched tricuspid aortic valve control participants (n = 20). Quantitative histopathology was conducted on BAV aorta tissue samples resected at surgery (n = 93), and correlation was performed between elastic fiber thickness and in vivo aortic WSS as continuous variables. Validation of elastic fiber thickness was achieved by correlation relative to tissue stiffness determined using biaxial biomechanical testing (n = 22 samples). RESULTS:Elastic fibers were thinner and WSS was higher along the greater curvature compared with other circumferential regions (vs anterior wall: P = .003 and P = .0001, respectively; lesser curvature: both P = .001). Increased regional WSS was associated with decreased elastic fiber thickness (r = -0.25; P = .02). Patient stratification with subanalysis showed an increase in the correlation between WSS and histopathology with aortic valve stenosis (r = -0.36; P = .002) and smaller aortic diameters (<4.5 cm: r = -0.39; P = .03). Elastic fiber thinning was associated with circumferential stiffness (r = -0.41; P = .06). CONCLUSIONS:For patients with BAV, increased aortic valve-mediated WSS is significantly associated with elastic fiber thinning, particularly with aortic valve stenosis and in earlier stages of aortopathy. Elastic fiber thinning correlates with impaired tissue biomechanics. These novel findings further implicate valve-mediated hemodynamics in the progression of BAV aortopathy.

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Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

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Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

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