Genetic testing after heart transplantation uncovers heritable disease and drives family screening

Moliner-Abós, Carlos; Cabrera Argaña, Diego; Belmar Cliville, David; Rivas, Sonia; Crespo-Leiro, María Generosa; Peña Hidalgo, Adrián; Garrido González, Ramón; Martín Marín, Pablo; Gómez Molina, Miriam; Lorca, Rebeca; Cárdenes León, Aridane; González-Vílchez, Francisco; Rodríguez Arias, Juan José; Basurte-Elorz, M. Teresa; Valverde, María; Larrañaga Moreira, José María; Antúnez-Ballesteros, Milena; Frutos, Fernando de; Rivas-Lasarte, Mercedes; Sobrino-Márquez, José Manuel; Garrido-Bravo, Iris P.; Díaz-Molina, Beatriz; Acosta Calero, Carmen; Goena-Vives, Cristina; García-Álvarez, Ana; Vilches, Silvia; García-Romero, Elena; Gómez-Bueno, Manuel; García-Pinilla, José Manuel; Alonso Fernández, Vanesa; Ochoa, Juan Pablo; Antonio-Ferrer, Marta de; Rodríguez-Santiago, Benjamín; Mirabet, Sonia

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https://hdl.handle.net/2183/49035

Genetic testing after heart transplantation uncovers heritable disease and drives family screening

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Identifiers

URI: https://hdl.handle.net/2183/49035

DOI: 10.1016/j.jacadv.2026.103043

Publication date

2026-08-03

Authors

Moliner-Abós, Carlos

Cabrera Argaña, Diego

Belmar Cliville, David

Rivas, Sonia

Crespo-Leiro, María Generosa

Peña Hidalgo, Adrián

Garrido González, Ramón

Martín Marín, Pablo

Gómez Molina, Miriam

Lorca, Rebeca

Bibliographic citation

Moliner-Abós C, Cabrera Argaña D, Belmar Cliville D, Rivas S, Crespo-Leiro MG, Peña Hidalgo A, Garrido Gonzalez R, Martín Marín P, Gómez Molina M, Lorca R, Cárdenes León A, González Vilchez F, Rodriguez Arias JJ, Basurte Elorz M, Valverde M, Larrañaga-Moreira JM, Antunez-Ballesteros M, de Frutos F, Rivas-Lasarte M, Manuel Sobrino Márquez J, Garrido Bravo IP, Diaz Molina B, Acosta Calero C, Goena-Vives C, García-Álvarez A, Vilches S, Garcia Romero E, Gomez Bueno M, Garcia Pinilla JM, Alonso Fernandez V, Ochoa JP, de Antonio-Ferrer M, Rodriguez-Santiago B, Mirabet-Pérez S. Genetic testing after heart transplantation uncovers heritable disease and drives family screening. JACC Adv. 2026 Jul 31;5(9):103043.

Abstract

[Abstract] Background. Genetic testing (GT) is established in ambulatory cardiomyopathy (CM), but its utility after heart transplantation (HTx) recipients remains poorly characterized. Objectives. 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. Methods. 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. Results. 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. Conclusions. 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.