Genetic variant spectrum in dilated and non-dilated left ventricular cardiomyopathy
T Barkan, H Baris Feldman, D Viskin, Y Topilsky, S KhouryAbstract
Background
The latest European Society of Cardiology (ESC) guidelines on cardiomyopathies introduced non-dilated left ventricular cardiomyopathy (NDLVC) as a distinct clinical phenotype within a phenotype-based classification framework. Despite growing recognition of this entity, data on its genetic architecture and its potential distinction from dilated cardiomyopathy (DCM) remain limited.
Objective
To describe and compare the spectrum of genetic variants in probands with NDLVC and DCM in a tertiary referral cardiomyopathy center.
Methods
We retrospectively reviewed probands with a diagnosis of DCM or NDLVC who were evaluated in our cardiomyopathy and cardio-genetic clinics between 2022 and 2025 and who underwent next-generation sequencing using either comprehensive cardio-genetic panels or whole-exome sequencing. Cardiac phenotypes were defined by cardiac magnetic resonance imaging according to current ESC guidelines. Genetic variants were classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUS) according to American College of Medical Genetics and Genomics (ACMG) criteria.
Results
A total of 84 probands were included: 46 (55%) with DCM and 38 (45%) with NDLVC. Relevant genetic variants were identified in 65 patients (77%) [37/46 (80%) with DCM vs. 28/38 (74%) with NDLVC]. At least one pathogenic or likely pathogenic (P/LP) variant was detected in 30 of 65 patients (46%) [17/37 (46%) with DCM vs. 13/28 (46%) with NDLVC]. The most frequent P/LP variants were in FLNC, found in 9/30 patients (30%) [5/17 (29%) with DCM vs 4/13 (31%) with NDLVC], followed by DSP 6/30 (20%) [3/17 (18%) vs. 3/13 (23%)], and TTN in 5/30 (17%) [2/17 (12%) vs. 2/13 (15%)].
Conclusion
In a dedicated cardiomyopathy and cardio-genetic clinic setting, genetic testing demonstrated a high diagnostic yield in both DCM and NDLVC, with substantial overlap in their genetic profiles. FLNC was the most frequently identified pathogenic/likely pathogenic gene in both groups, followed by DSP and TTN, indicating a largely overlapping genotype across these phenotypes.Variant Distrubtion in DCM and NDLVCP/PL Genetic Variants