Associations of Pathogenic Sequence Variants and Copy Number Variants with Cardiovascular and Major Clinical Outcomes in Adults with Congenital Heart Disease
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Background
Genetic abnormalities play a role in the phenotypic heterogeneity of congenital heart disease (CHD), but their associations with long-term cardiovascular outcomes in adults with congenital heart disease (ACHD) remain inadequately defined. This study examined the correlations between pathogenic sequence variations and copy number variants (CNVs) with cardiovascular and significant clinical outcomes in persons suffering from CHD.
Methods
This prospective observational cohort study included 1,000 adults with structurally confirmed CHD recruited from a tertiary care centre in Noida, India, between January 2022 and January 2026, with follow-up through August 2026. Those who have consented received exome sequencing and chromosomal microarray assessment and were categorized into four distinct, non-overlapping groups: reference, sequence-variant-only, CNV-only, and dual-positive. The primary outcome was the time to the first occurrence of any of the following events: cardiovascular death, unplanned heart failure hospitalization, resuscitated cardiac arrest, qualifying sustained ventricular tachyarrhythmia, heart transplantation or durable mechanical circulatory support. Appropriate statistical analysis was performed and results were obtained.
Results
The results showed that among the participants recruited, 800 were in the reference group, 120 had sequence variants alone, 60 had CNVs alone, and 20 had both sequence variants and CNVs. Over a median follow-up of 4.2 years, the primary outcome occurred in 12.0%, 20.0%, 25.0%, and 30.0% of participants, respectively. In the fully adjusted model, the sequence-variant-only group had an HR of 1.65 (95% CI, 1.01–2.69; nominal p = 0.0455), while the CNV-only group had an HR of 1.92 (95% CI, 1.04–3.52; nominal p = 0.0360), compared with the reference group. After Holm adjustment, neither association reached statistical significance (adjusted p = 0.072 for both comparisons). The dual-positive group had an HR of 2.12 (95% CI, 0.83–5.42; p = 0.1182). Extracardiac congenital anomalies and neurological disorders were more prevalent in those with genetic variations. Nonetheless, the secondary outcomes revealed no statistically significant correlations.
Conclusions
Pathogenic sequence variations and CNVs exhibited a numerically elevated adjusted risk for the primary cardiovascular composite outcome in ACHD, however neither primary association reached statistical significance after multiplicity adjustment. The findings highlight the potential significance of genetic diversity concerning clinical variability in ACHD, however they do not confirm independent prognostic significance.
