Congenital heart disease (CHD) is the most common class of major malformations in humans. The historical association with large chromosomal abnormalities foreshadowed the role of submicroscopic rare copy number variations (CNVs) as important genetic causes of CHD. Recent studies have provided robust evidence for these structural variants as genome-wide contributors to all forms of CHD, including CHD that appears isolated without extra-cardiac features. Overall, a CNV-related molecular diagnosis can be made in up to one in eight patients with CHD. These include de novo and inherited variants at established (chromosome 22q11. 2), emerging (chromosome 1q21. 1), and novel loci across the genome. Variable expression of rare CNVs provides support for the notion of a genetic spectrum of CHD that crosses traditional anatomic classification boundaries. Clinical genetic testing using genome-wide technologies (eg, chromosomal microarray analysis) is increasingly employed in prenatal, paediatric and adult settings. CNV discoveries in CHD have translated to changes to clinical management, prognostication and genetic counselling. The convergence of findings at individual gene and at pathway levels is shedding light on the mechanisms that govern human cardiac morphogenesis. These clinical and research advances are helping to inform whole-genome sequencing, the next logical step in delineating the genetic architecture of CHD.

Genome-wide rare copy number variation (CNV) is now recognised as an important contributor to congenital heart disease (CHD). This review surveys recent advances in the field of structural genomics, with the goal of informing both the clinical translation of findings and the anticipated future wave of whole-genome sequencing (WGS) studies. Herein, CHD refers to major malformations of the heart or great vessels present at birth. Cardiomyopathies, vasculopathies and cardiac arrhythmias are excluded. The focus is on findings from large-scale genome-wide studies of submicroscopic germline CNV, and not on chromosomal abnormalities detectable on karyotype, case reports or small case series of individual CNVs, or deletion/duplication analyses of individual genes.