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.

Fetal cardiac abnormalities: Genetic etiologies to be considered

“…Counselling should describe what it is already known about the phenotype associated with that CNV. It should also emphasize the potential for considerable variability in the type and severity of manifestations and/or incomplete penetrance . In some cases, parents will carry the same CNV.…”

Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

“…For example, the discovery of congenital heart disease (CHD) increases the risk for a 22q11.2 deletion substantially. Prevalence estimates for the 22q11.2 deletion include 5–10% of ventricular septal defect (VSD), ~15% of tetralogy of Fallot, ~33% of truncus arteriosus, and ~50% of interrupted aortic arch type B . An anomaly of aortic arch laterality or branching may hint at an underlying 22q11.2 deletion, even in the absence of a major intracardiac defect .…”

“…An anomaly of aortic arch laterality or branching may hint at an underlying 22q11.2 deletion, even in the absence of a major intracardiac defect . Although conotruncal and select other anomalies are classically described, all types of CHD have been seen in association with 22q11.2 deletions . If present (estimated 40–75% of patients with 22q11.2DS), CHD severity can range from non‐viable to subclinical (e.g.…”

“…Prevalence estimates for the 22q11.2 deletion include 5-10% of ventricular septal defect (VSD),~15% of tetralogy of Fallot,~33% of truncus arteriosus, and~50% of interrupted aortic arch type B. 12,16,17 An anomaly of aortic arch laterality or branching may hint at an underlying 22q11.2 deletion, even in the absence of a major intracardiac defect. 16 Although conotruncal and select other anomalies are classically described, all types of CHD have been seen in association with 22q11.2 deletions.…”

“…16 Although conotruncal and select other anomalies are classically described, all types of CHD have been seen in association with 22q11.2 deletions. 12,17,18 If present (estimated 40-75% of patients with 22q11.2DS), 12,19 CHD severity can range from non-viable to subclinical (e.g. spontaneously closing VSD).…”