Key result
Whole-genome sequencing identifies pathogenic variants in ~33% of heart transplant recipients, led by TTN.
Cohort (n=1,186)
No
Whole-genome sequencing identifies pathogenic or likely pathogenic variants in 33% of adult heart transplant recipients, providing critical insights for genetic diagnosis, risk stratification, and family screening in end-stage heart failure.
Background End-stage heart failure (ESHF) is a primary driver of cardiovascular morbidity and mortality, with heart transplantation (HTx) serving as the gold-standard treatment for refractory cases. While rare pathogenic DNA variants are known contributors to cardiomyopathy, the comprehensive whole-genome landscape of HTx recipients and its correlation with clinical phenotypes remain insufficiently characterized. Objectives This study aimed to delineate the spectrum and prevalence of rare pathogenic and likely pathogenic (P/LP) variants in cardiovascular disease-associated genes among ESHF patients undergoing HTx and to evaluate their clinical impact on pre-transplant phenotypes. Methods Whole-genome sequencing (WGS) was performed on a single-center cohort of 1,186 HTx recipients. Variants, including SNPs and INDELs, were annotated using ANNOVAR and classified according to ACMG/AMP guidelines. Results Among the 1,186 heart transplantation recipients, the underlying etiologies included dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), valvular heart disease (VHD), and other causes; DCM was the most common indication for transplantation (n = 704). Age at transplantation differed across etiologies, with the oldest transplant age observed in ICM followed by DCM and the youngest in ARVC. Overall, 389 patients (33%) carried at least one pathogenic or likely pathogenic (P/LP) variant. The most frequently implicated gene was TTN, accounting for 29% of all P/LP variants. Across genotype-positive patients, carriers of FLNC, LMNA, DES, and DSP exhibited more prominent myocardial fibrosis (higher late gadolinium enhancement burden) and a higher frequency of malignant ventricular arrhythmia (MVA) events, whereas TTN variant carriers had the highest age at transplantation. Notably, genotype-negative patients did not uniformly display the mildest phenotype with respect to fibrosis, transplant age, or MVA burden, suggesting that a substantial subset may harbor unresolved genetic contributors not captured by current interpretation frameworks. Conclusions WGS identifies P/LP variants in a substantial proportion of adult HTx recipients. These genomic architectures provide critical insights into disease mechanisms, facilitating improved genetic diagnosis, risk stratification, and proactive family screening in end-stage heart failure.
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Xu et al. (2026) conducted a cohort in End-stage heart failure undergoing heart transplantation (n=1,186). Whole-genome sequencing (rare pathogenic/likely pathogenic variants) vs. Genotype-negative heart transplantation recipients was evaluated on Prevalence of rare pathogenic and likely pathogenic (P/LP) variants in cardiovascular disease-associated genes. Whole-genome sequencing identified pathogenic or likely pathogenic variants in 33% (389/1,186) of heart transplant recipients, with TTN accounting for 29% of all variants.
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