Genetic Testing After Heart Transplantation Uncovers Heritable Disease and Drives Family Screening

Genetic testing (GT) is established in ambulatory cardiomyopathy (CM), but its utility after heart transplantation (HTx) recipients remains poorly characterized.

This study aimed to evaluate the clinical utility of GT in adult HTx recipients with CM, focusing on etiologic reclassification, family cascade screening, and the genetic architecture of end-stage disease.

GenbaseHTx is a nationwide, multicenter retrospective study of adult HTx recipients transplanted for CM across 12 Spanish centers (2010-2023). GT results were centrally adjudicated using American College of Medical Genetics and Genomics criteria. Outcomes included prevalence of pathogenic/likely pathogenic variants, etiologic reclassification after GT, and cascade screening activation.

Among 657 HTx recipients, a pathogenic/likely pathogenic variant was identified in 53% (351/657). GT led to etiologic reclassification in 35% (231/657) (42% when performed post-HTx -106/253-). Family screening (performed in 69% of families -224/328-) identified affected relatives in 22% (19/90) of genotype-negative and 42% (49/107) of genotype-positive cases. Notably, a genetic etiology was identified in 36% (15/42) of CM initially attributed to acquired or "second-hit" causes. In dilated cardiomyopathy, the genetic architecture of transplanted patients differed from ambulatory cohorts, with lower TTN variant prevalence and enrichment of arrhythmogenic genes.

GT remains clinically actionable after HTx, enabling etiologic reclassification and driving cascade screening. These findings support systematic GT in HTx recipients with CM, including those with prior environmental triggers or second-hit etiologies, and regardless of time from transplantation.