Utility of genetic testing in heart transplant recipients: a systematic review and meta-analysis

Genetic cardiomyopathies commonly cause end-stage heart failure, yet genetic testing is inconsistently applied in heart transplant recipients. Identifying pathogenic/likely pathogenic (P/LP) variants clarifies etiology and informs familial risk, but data on diagnostic yield are limited. We performed a meta-analysis to quantify genetic testing yield in heart transplant recipients and implications for cascade testing. MEDLINE and Embase were searched for studies examining cardiomyopathy-focused genetic testing in heart transplant recipients. Pooled P/LP cardiomyopathy variant yields were estimated using random-effects models, stratified by cardiomyopathy phenotype. Cascade testing outcomes were summarized. Eleven studies met inclusion criteria. Overall, 32% (95% CI: 21-46%) of heart transplant recipients carried a P/LP variant. Yield was highest in non-ischemic cardiomyopathy (34%, 95% CI: 24-47%) and non-ischemic dilated cardiomyopathy cohorts (29%, 95% CI: 12-54%), and lowest in ischemic cardiomyopathy cohorts (8%, 95% CI: 4-18%). Heterogeneity ranged from I² 35% to 92%. Among studies reporting cascade testing outcomes, 52-92% of families underwent testing; 30-40% of relatives had P/LP variants, 15-69% of which demonstrated a phenotypic CM. While exact estimates should be interpreted cautiously given heterogeneity across cohorts, the consistency of findings suggests meaningful clinical relevance. Cardiomyopathy-focused genetic testing identifies P/LP variants in many heart transplant recipients, with important implications for cascade testing, supporting integration of cardiomyopathy-related genetic evaluation into heart transplant programs.