The importance of copy number variation in congenital heart disease

Abstract

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 (e.g., 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.

Figure 1

Spectrum of human CHD. CHD is an umbrella term for a range of malformations of the heart and great vessels (aorta and pulmonary arteries). There exist multiple clinically and anatomically discrete lesions, of differing incidence and severity. See text and associated references for details. (a) Labelled diagram of the structurally normal human heart. (b) Examples of some congenital cardiac lesions, based on anatomy. For a full list of congenital cardiac defects, consult a congenital cardiology textbook. Multiple congenital defects may be present within an individual. (c) Labelled diagram of one specific form of CHD: tetralogy of Fallot (TOF).

Figure 2

Examples of CNV and associated disease mechanisms. (a) Normal diploid status and two examples of CNV (a simple deletion and a tandem duplication). Not pictured are the diverse other forms of CNV, including non-contiguous insertions, higher-order copy number changes (multi-allelic CNV), and more complex rearrangements. CNVs may involve no, one or multiple genomic elements. (b) Selected mechanisms underlying disease effects of copy number losses (deletions). A gene is indicated by a contiguous monochromatic set of rectangles, and a regulatory element (e.g., promoter) by an oval. The definition of ‘gene’ extends beyond protein-coding genes to potentially include noncoding elements like microRNAs and long noncoding RNAs. Of note, duplications can effect change through increased copy number of a dosage sensitive gene (not pictured) or via the mechanisms depicted for deletions (e.g., via disruption at a breakpoint or partial intragenic duplication). Inspired by Figure 1 in ref. and Figure 2 in ref. .

Figure 3

Prevalence of 1q21.1 duplications in cohorts with TOF. Box size is proportional to study size: n=33, n=510, n=948, n=433, n=81, n=68 and n=57. The blue diamond represents the combined prevalence of 1q21.1 duplications in a total of 2130 subjects with TOF, and the diamond width corresponds to 95% confidence interval bounds. In contrast, 1q21.1 duplications are rare in control populations (see text).