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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:Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.Author summaryBicuspid aortic valve (BAV) is the most common form of congenital heart disease and can lead to long-term complications such as aortic stenosis, aortic regurgitation, or thoracic aortic aneurysms. Most BAV-related complications arise in late adulthood, but 10-15% of individuals with BAV develop early onset complications before age 30. Copy number variants (CNVs) are genomic structural variations that have been previously implicated in some types of congenital heart disease, including BAV. Here we demonstrate that individuals with early onset complications of BAV are enriched for specific rare CNVs compared to individuals with late-onset BAV disease. We also describe novel CNVs involving DSCAM , a gene on chromosome 21 that has not previously been associated with the development of BAV. These results may lead to improved risk stratification and targeted therapies for BAV patients.

Dataset Information

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

Publications

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

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