Comprehensive pathological and genetic investigation of four young adults with a short QT interval and sudden unexpected death

While structural heart abnormalities are not typically associated with short QT syndrome (SQTS)-related sudden unexpected death, few autopsy studies have examined the underlying pathology and genetic factors of SQTS. Therefore, we conducted comprehensive pathological examinations and whole-exome sequencing in four men (aged 24, 28, 31, and 45 years) with sudden unexpected death and a short QT interval (sQT). No variants were identified in genes currently known to be associated with SQTS. An enrichment analysis was performed to identify potential genetic causes and mechanisms. None of the men had a history of cardiovascular disease, familial sudden death, or arrhythmia. Rare variants in SCN10A, ANK2, KCNQ2, and CACNA1H were detected, potentially associated with cardiac electrophysiology. One case showed apical hypertrophic cardiomyopathy with a rare PLEC variant. The other three showed left ventricular hypertrabeculation with poor compaction, deep recess formation, myocardial fibrosis, micronecrosis, and minimal inflammatory cell infiltration. The enrichment analysis showed that these variants were associated with cardiac electrophysiology and morphogenesis. These results showed that individuals with sQT may be at risk of sudden death even without a clinical or family history. This risk may be increased by cardiomyopathy-related gene variants in preclinical or early disease stages. Electrocardiographic evaluation to identify sQT cases followed by morphological and genetic evaluations improves the assessment of a sudden death risk in individuals with sQT.