Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant

Background Etiological identification in young survivors of exercise-induced sudden cardiac death (SCD) frequently encounter challenges due to phenotype-genotype incongruity. Case presentation: We present a 21-year-old female survivor of aborted SCD caused by exercise-triggered ventricular fibrillation (VF). Comprehensive imaging studies ( echocardiography and cardiac magnetic resonance ) revealed no structural abnormalities. Ambulatory electrocardiography demonstrated prolonged QTc intervals (Schwartz score: 4.5), fulfilling the diagnostic criteria for long QT syndrome (LQTS). Intriguingly, the electrocardiographic findings also satisfied depolarization/repolarization abnormality indices per the 2010 revised Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole-exome sequencing identified heterozygous variants in the DSP (desmoplakin) and CFHR5 (complement factor H-related 5) genes, whereas no pathogenic variants were detected in 17 canonical LQTS-associated genes. Despite favourable outcomes with beta-blocker therapy, the exact trigger for VF remains elusive: the DSP variant suggests potential ARVC-related myocardial electrical substrate abnormalities, whereas the pathogenic importance of the CFHR5 variant in cardiomyopathy remains unestablished. Furthermore, the borderline LQTS phenotype lacked definitive genetic corroboration. Conclusions This case illustrates a "tripartite dissociation" among electrophysiological phenotype, cardiac structure, and genetic findings, challenging conventional disease classification frameworks in young SCD survivors. Prioritizing functional studies to investigate potential polygenic synergy in arrhythmogenesis may advance diagnostic paradigms and personalized SCD prevention strategies for atypical cases.