Elsevier

American Heart Journal

Volume 254, December 2022, Pages 166-171
American Heart Journal

Research Letter
Insights into the genetic architecture underlying complex, critical congenital heart disease.

https://doi.org/10.1016/j.ahj.2022.09.006Get rights and content

Abstract

Congenital heart disease (CHD) has a multifactorial aetiology, raising the possibility of an underlying genetic burden, predisposing to disease but also variable expression, including variation in disease severity, and incomplete penetrance. Using whole genome sequencing (WGS), the findings of this study, indicate that complex, critical CHD is distinct from other types of disease due to increased genetic burden in common variation, specifically among established CHD genes. Additionally, these findings highlight associations with regulatory genes and environmental “stressors” in the final presentation of disease.

Section snippets

Methods

Participants with severe CHD (defined as those with complex, critical CHD requiring neonatal surgical intervention), were compared to participants with CHD requiring surgical intervention after the neonatal period. Patients with known syndromes were excluded. Principal component analyses were conducted to confirm sample ethnicity and enable direct comparisons between study participants. Ethical approval was obtained from the Sydney Children's Hospitals Network Human Research Ethics Committee

Sources of funding

This work conducted by GMB was supported by a National Heart Foundation of Australia Postdoctoral Fellowship (101894). EG is supported by a NSW Health Early-Mid Career Fellowship, a National Heart Foundation of Australia Future Leader Fellowship (101204). SLD is the recipient of a National Health and Medical Research Council (NHMRC) Project Grant ID1102373, Principal Research Fellowship ID1135886, and NHMRC Synergy Grant ID1181325, and a NSW Health Cardiovascular Research Capacity Program

Results

Following principal component analyses, 28 participants were removed due to mismatched ethnicity or poor data quality. The final 62 participants comprised 23 with severe CHD and 39 with other clinically relevant CHD. There were no significant differences between the 2 groups in terms of clinical and demographic variables; however, as expected there was a significant difference in CHD type (P< .001), with the severe cases comprising significantly more patients with single ventricle pathology and

Discussion

These findings suggest that the genetic architecture of complex, critical CHD is distinct from other types of CHD due to a significant increase in common variation, specifically among established CHD genes. In comparison, other types of CHD comprise more rare and low-frequency variants, possibly of greater effect size (Figure 1D). This supports a polygenic model of inheritance, implicating multiple common variants, each conferring a small effect, in the development of critical, complex CHD.

Declarations of interest

None.

Conflict of interest

None reported.

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