Comparative whole-exome sequencing of ambulatory patients and transplant recipients with idiopathic dilated...

Idiopathic dilated cardiomyopathy (DCM) is a major cause of advanced heart failure and heart transplantation (HTx), yet the genetic correlates of progression to HTx and transplant-relevant arrhythmic phenotypes remain incompletely defined. We examined the genetics of idiopathic DCM in a Korean population, focusing on HTx/death and arrhythmic outcomes, to identify adverse outcome-linked genotype-phenotype associations.

Whole-exome sequencing was performed in 202 Korean patients with idiopathic DCM, including 56 HTx recipients and 146 ambulatory patients, and compared the findings with 1093 population-based controls. Genotype-phenotype correlations were analyzed for major clinical outcomes, including HTx, death, arrhythmias, and left ventricular functional recovery.

Pathogenic/likely pathogenic variants were identified in 32% of patients (38% in HTx vs 30% in ambulatory patients). TTN was the most frequently affected gene overall (12%), but LMNA variants predominated in HTx recipients (20% vs 4%, p = 0.001). LMNA carriers showed substantially higher odds of HTx/death (OR 14.65, 95% CI 3.32-139.31; FDR p<0.001), and strong association with arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation. Both missense and loss-of-function LMNA variants were associated with adverse outcomes. In contrast, TNNT2 variants were observed exclusively in ambulatory patients and identified a favorable functional-recovery phenotype, with a greater likelihood of LVEF recovery ≥10 percentage points (OR 6.03, 95% CI 1.52-28.71; FDR p = 0.016).

LMNA variants mark a high-risk transplant-trajectory phenotype in Korean idiopathic DCM. Genetic testing may aid early identification and management of candidates for advanced HF therapies, including HTx and durable MCS.