Associations of Pathogenic Sequence Variants and Copy Number Variants with Cardiovascular and Major Clinical Outcomes in Adults with Congenital Heart Disease

Background: Genetic abnormalities contribute to the phenotypic heterogeneity of congenital heart disease, yet their prognostic significance in adults with congenital heart disease remains incompletely understood. We examined the associations of pathogenic sequence variants and copy number variants (CNVs) with cardiovascular and major clinical outcomes in ACHD. Methods: In this prospective observational cohort study, 1,000 adults with structurally confirmed CHD were recruited from a tertiary care center in Noida, India, between January 2022 and January 2026 and followed through August 2026. Participants underwent exome sequencing and chromosomal microarray analysis and were classified into four mutually exclusive groups: reference, sequence-variant-only, CNV-only, and dual-positive. The primary outcome was time to first occurrence of a composite of cardiovascular death, unplanned heart failure hospitalization, resuscitated cardiac arrest, sustained ventricular tachyarrhythmia, heart transplantation, or durable mechanical circulatory support. Associations were evaluated using multivariable Cox regression. Results: Of 1,000 participants, 800 comprised the reference group, 120 had sequence variants only, 60 had CNVs only, 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 fully adjusted analyses, the sequence-variant-only group had a higher risk of the primary outcome versus the reference group (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.01?2.69; p=0.0455). The CNV-only group had an HR of 1.92 (95% CI, 1.04?3.52; p=0.0360). Neither association remained significant after Holm adjustment (adjusted p=0.072 for both). 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 among individuals with genetic variants, while secondary outcomes showed no significant associations. Conclusions: Pathogenic sequence variants and CNVs were associated with numerically higher risks of adverse cardiovascular outcomes in ACHD, but independent prognostic significance was not established after adjustment for multiple testing.