Without genetic testing, 1 in 4 DCM/NDLVC patients are wrongly risk-stratified in the current era of personalised care

Background Recent ESC cardiomyopathy guidelines introduced the concept of NDLVC and positioned genotype as a key determinant of arrhythmic risk stratification, highlighting specific high-risk genes as independent risk modifiers. The real-world clinical impact of systematic genetic testing across the DCM/NDLVC spectrum remains incompletely defined. Methods We prospectively enrolled 121 consecutive probands with DCM or NDLVC referred to our inherited cardiomyopathy program (2019-2022). All patients underwent standardized clinical assessment and panel-based genetic testing. Variants were classified per ACMG/AMP criteria. High-risk genes were defined per ESC guidelines (LMNA, PLN, FLNC, RBM20, SCN5A, TMEM43, DSP). Arrhythmic phenotype was defined as complex ventricular arrhythmias (NSVT, VT, appropriate ICD shocks). The aim was to evaluate the clinical impact of genetic testing on arrhythmic risk stratification and primary prevention ICD decision-making. Results The cohort included 121 probands (59% male, mean age 37 ± 15.4 years; mean LVEF 47 ± 10%), of whom 50 had DCM and 71 NDLVC. Extensive fibrosis was present in 13%. A P/LP variant was identified in 45% of the probands. High-risk gene variants were present in 23% of the total cohort; 30% in NDLVC patients and in 12% of DCM patients. An arrhythmic phenotype was documented in 49 probands (41%). High-risk gene variants were more prevalent among arrhythmic phenotypes (39% vs. 11%, p=0.001). In 24 probands, high-risk genotype upgraded arrhythmic risk classification beyond LVEF-based criteria. Two individuals were identified with syndromic/specific phenocopies. Cascade screening reclassified 25 additional relatives to a higher arrhythmic risk category. Conclusions Systematic genetic testing identified P/LP variants in 45% of DCM/NDLVC probands, with 23% carrying ESC-designated high-risk gene variants. High-risk genotypes were significantly associated with arrhythmic phenotype and had a direct, quantifiable impact on risk stratification and ICD decision-making in probands and families. Omission of genetic testing represents a failure to apply contemporary stratification tools to a population in whom genotype is a principal determinant of arrhythmic risk. Routine genotype-informed evaluation should be considered a fundamental component of personalised care in DCM and NDLVC.