Systematic assessment of DSP missense variants in a cohort of patients with left ventricular cardiomyopathy
M Bergier, A Esteve-Garcia, C Diez-Lopez, J Gonzalez-Costello, J Comin-Colet, F de FrutosAbstract
Background
Truncating variants in desmoplakin (DSP) are an established cause of dilated (DCM) and arrhythmogenic cardiomyopathy (ACM) with left ventricular (LV) involvement. The clinical relevance of missense DSP variants remains uncertain.
Purpose
To assess the prevalence and pathogenicity of missense DSP variants in a large cohort of LV cardiomyopathy patients.
Methods
We retrospectively analyzed probands ≥18 years with DCM (LV ejection fraction <50%) or ACM with LV involvement (late gadolinium enhancement on cardiac magnetic resonance) who underwent next-generation sequencing (2016–2025) in one centre and were carriers of rare missense DSP variants. Prevalence of rare DSP missense variants in DCM/ACM-LV patients was compared with an ancestry-matched control group of HCM probands, all sequenced at the same center. Rare variants were defined as those with a minor allele frequency under 0.001 in gnomAD v2. Odds Ratios were calculated, and statistical significance was assessed using a chi-square test.
Results
Among 816 probands (736 DCM, 80 ACM-LV), 44 carried DSP variants: 17 truncating and 27 missense. After exclusions, 21 probands (2.57%) with isolated missense variants were analysed. Mean age was 53.2 ± 17.0 years; 66.7% were male. A low population frequency was observed in 90.5% of the variants, and an in-silico predictor suggested a deleterious effect (REVEL score > 0.70) for three variants. Only four variants had been previously reported and cosegregation was not observed in any of the families. Following reassessment, all variants remained classified as variants of uncertain significance (VUS). Rare missense DSP variants were not overrepresented in DCM/ACM-LV probands compared with ancestry-matched HCM probands (OR 1.04 95% CI 0.55–1.99; P = 0.90).
Conclusions
In a large cohort of patients with LV cardiomyopathy, isolated rare DSP missense variants remained classified as VUS after systematic reassessment and showed no enrichment compared with ancestry-matched HCM controls. These findings suggest a limited contribution of isolated DSP missense variants to disease burden and support a cautious approach to their clinical interpretation. Dedicated functional and large-scale population studies are warranted to clarify their pathogenicity.FlowchartMissense variants in DSP (NM_004415.4)