Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve

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 a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 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 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

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Publication Details

Journal
PLoS ONE
Published
2024-09-06
DOI
https://doi.org/10.1371/journal.pone.0304514
Citations
6
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
1.40

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article

Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve

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6 citations
PLoS ONE
Congenital heart defects research
1.40
article

Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve

Dawn S. Hui, Margot De Marco, Anthony Caffarelli, Anna Sabaté-Rotés, Siddharth K. Prakash, Ilenia Foffa, Yuli Y. Kim, Anji T. Yetman, Justin T. Tretter, Steven Grant Carlisle, Kim L. McBride, Malenka M. Bissell, Rodolfo Citro, Dianna M. Milewicz, Julie De Backer, Héctor I. Michelena, Lisa Bianco, Maria Grazia Andreassi, Laura Muiño Mosquera, Simon C. Body, Hasan Albasha, Dongchuan Guo
article en
6 citations

Abstract

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 a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 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 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

PLoS ONEVol. 19(9)
University College Dublin (IE), Boston University (US), Hoag Memorial Hospital Presbyterian (US), University of Leeds (GB), Cleveland Clinic (US), University of Salerno (IT), Mayo Clinic (US), The University of Texas at San Antonio Health Science Center (US), University of Calgary (CA), Ghent University Hospital (BE), WinnMed (US), Istituto di Fisiologia Clinica (IT), Vall d'Hebron Hospital Universitari (ES), Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT), University of Nebraska Medical Center (US), University of Pennsylvania (US), The University of Texas Health Science Center at Houston (US)
University of Texas at Austin, Department of Mechanical Engineering, University of Texas at Austin, National Heart, Lung, and Blood Institute
Good health and well-being
Openalex Percentile: Top 19%
Congenital heart defects research
1.40
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