RESUMEN
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.
Asunto(s)
Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Variaciones en el Número de Copia de ADN , Enfermedades de las Válvulas Cardíacas , Polimorfismo de Nucleótido Simple , Humanos , Variaciones en el Número de Copia de ADN/genética , Válvula Aórtica/anomalías , Válvula Aórtica/patología , Enfermedad de la Válvula Aórtica Bicúspide/genética , Enfermedades de las Válvulas Cardíacas/genética , Masculino , Femenino , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Adulto , Estudios de Casos y Controles , Anciano , Enfermedad de la Válvula Aórtica/genética , Factor de Transcripción GATA4/genética , Estudio de Asociación del Genoma CompletoRESUMEN
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.