Genetic testing in 449 dilated cardiomyopathy patients identified pathogenic or likely pathogenic variants in 13.8% of cases, predominantly in the TTN gene.
In an unselected clinical cohort of dilated cardiomyopathy patients, standard genetic testing yields a definitive molecular diagnosis in only 13.8% of cases, highlighting the multifactorial nature of the disease and the need for expanded diagnostic approaches.
Absolute Event Rate: 0% vs 0%
Abstract Background Genetic testing in dilated cardiomyopathy (DCM) identifies pathogenic variants in 13-40% of cases depending on cohort selection and testing method1−3. Recent evidence emphasizes genotype-specific risk stratification4, yet the genetic landscape remains incompletely characterized in unselected clinical cohorts. Purpose To comprehensively characterize the genetic spectrum, diagnostic yield, and variant burden in a large DCM cohort from a single tertiary center over 27 years. Methods We analyzed 449 consecutive DCM patients referred to our genetics laboratory (1998-2025): due to technological evolution, 139 patients (31%) underwent targeted Sanger sequencing (primarily pre-2019) and 309 (69%) next-generation sequencing panel testing (post-2019). Variants were classified according to ACMG/AMP guidelines5. Following our previously published approach6, we sub-classified variants of uncertain significance (VUS) with strong pathogenic evidence (VUS/LP) for exploratory analysis. Results The cohort comprised 301 males (67%) and 148 females (33%), M:F ratio 2.03:1. Median age was 55 years (IQR 41-64, range 0-86). Age distribution showed 3.1% pediatric (18 years), 24.5% young adults (18-40 years), peak prevalence at 51-60 years (25.2%), and 12.9% elderly (70 years). Standard ACMG criteria identified pathogenic/likely pathogenic variants in 62 patients (13.8%, 95%CI: 10.7-17.0%), with no gender difference (males 13.6% vs females 14.2%, p=0.88). TTN predominated (20 patients, 32.3%), followed by LMNA (9, 14.5%), RBM20 (5, 8.1%), MYH7 (4, 6.5%), TNNT2 and BAG3 (each 3, 4.8%), consistent with ESC guidelines7. Sub-classification of VUS identified 12 additional patients, increasing yield to 74 (16.5%). Gene-specific increments were: TNNT2 (3→7, +133%), TTN (20→23, +15%), DSP (2→4, +100%), DES (1→3, +200%). Notably, LMNA, RBM20, and BAG3 showed no VUS meeting reclassification criteria, suggesting definitive variant interpretation in these established high-risk genes47. Twenty-one patients (4.7%) harbored multiple variants (18 with two, 1 with three, 2 with five variants), with DSP-MYBPC3 and DES-TTN as recurring combinations (each n=2). Variant burden analysis revealed 386 patients (86.2%) with no P/LP variants, 57 (12.7%) with one, and only 4 (0.9%) with multiple P/LP variants. With modified criteria, 13 patients (2.9%) carried multiple variants. Notably, TTN c.69936CG (p.Tyr23312*) was identified in 4 unrelated patients, absent from population databases and previously reported in our sudden cardiac death cohort6, suggesting a regional founder variant with implications for both DCM and arrhythmic risk. NGS demonstrated superior yield versus Sanger (15.9% vs 9.4%, OR=1.83, 95%CI: 0.95-3.52, p=0.076). Conclusions This single tertiary center experience reveals that despite comprehensive testing, only 13.8% of DCM patients receive a molecular diagnosis,reflecting challenges in unselected clinical practice. While VUS sub-classification modestly increases yield to 16.5%, the vast majority of patients remain without genetic explanation, highlighting the complex multifactorial nature of DCM. The identification of TTN c.69936CG in both DCM and sudden death cohorts highlights the importance of variant-specific risk assessment. With 86% of patients remaining genetically unexplained, our findings support systematic reanalysis of historical cases and periodic variant reinterpretation, while underscoring the need for expanded gene discovery and complementary diagnostic approaches.
Martina et al. (Sun,) reported a other. Genetic testing in 449 dilated cardiomyopathy patients identified pathogenic or likely pathogenic variants in 13.8% of cases, predominantly in the TTN gene.