Diagnostic Yield of Genetic Testing in Heart Transplant Recipients with Non-Ischemic Cardiomyopathy: A Single-Centre Cohort Study

Background Cardiomyopathy genetic testing is recommended for patients with non-ischemic cardiomyopathy (NICM) but is inconsistently applied once a patient has reached end-stage disease and undergone heart transplantation. Whether a transplant program can systematically test its existing NICM cohort, and what completion rate is achievable when testing is operationalized in clinic rather than offered ad hoc, is not well characterized. Methods We studied all 73 adults followed in the Southern Alberta Transplant Program after transplantation for non-ischemic cardiomyopathy (NICM): dilated (DCM), non-dilated left ventricular (NDLVC), restrictive, or hypertrophic (HCM). Cardiomyopathy genetic testing was offered as a program-wide initiative and performed in adulthood using clinically validated multigene panels. Variants were classified by ACMG/AMP criteria; pathogenic or likely pathogenic (P/LP) variants interpreted as explanatory for the recipient's cardiomyopathy were counted as diagnostic. Single heterozygous P/LP variants in autosomal recessive genes were interpreted as carrier findings and not counted toward yield. Yields are reported with Wilson 95% confidence intervals (CIs); the childhood- versus adult-transplant comparison was tested with Fisher's exact test. Results Of 71 eligible patients, 27 (38.0%) had a genetic-testing result before the 12-month operational window; of the 44 offered testing during the window, 37 completed it (84.1%), raising cohort testing coverage to 90.1% (64/71). A diagnostic pathogenic or likely pathogenic (P/LP) variant was identified in 28 of 64 tested patients (43.8%; 95% CI 32.3–55.9%); a sensitivity analysis restricted to the 36 patients tested with the comprehensive Invitae 121-gene panel yielded an indistinguishable 38.9% (14/36; 95% CI 24.8–55.1%), with no evidence that variation in panel breadth materially biased the overall estimate. Two additional patients carried a single heterozygous P/LP variant in an autosomal recessive gene (carrier findings, not counted). Yield was higher in patients transplanted in childhood (10/14, 71.4%) than in adulthood (18/50, 36.0%; Fisher's exact p=0.031). TTN was the most frequent gene (7 P/LP), followed by LMNA , PKP2 , and MYH7 (3 each). Conclusions A 12-month program-wide initiative raised cardiomyopathy genetic testing coverage in an existing NICM heart transplant cohort from 38% to 90% by embedding testing in routine transplant clinic visits. The diagnostic yield among tested patients (43.8%) was consistent with published estimates and similar when restricted to the most comprehensive panel, with markedly higher yield in patients transplanted in childhood. These findings provide a reproducible operational template for transplant programs seeking to close the implementation gap in cardiomyopathy genetic evaluation and to enable cascade testing of at-risk relatives.