Copy-number variation in congenital heart disease

Genomic copy-number variants (CNVs) contribute to as many congenital heart disease (CHD) cases (10-15%) as chromosomal aberrations or single-gene mutations and influence clinical outcomes. CNVs in a few genomic hotspots (1q21.1, 2q13, 8p23.1, 11q24, 15q11.2, 16p11.2, and 22q11.2) are recurrently enriched in CHD cohorts and affect dosage-sensitive transcriptional regulators that are required for cardiac development. Reduced penetrance and pleiotropic effects on brain and heart development are common features of these CNVs. Therefore, additional genetic 'hits,' such as a second CNV or gene mutation, are probably required to cause CHD in most cases. Integrative analysis of CNVs, genome sequence, epigenetic alterations, and gene function will be required to delineate the complete genetic landscape of CHD.