Comprehensive Pathologic and Genetic Investigation of Four Young Adults with a Short QT Interval and Sudden Unexpected Death.

Although 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, comprehensive pathologic examinations and whole-exome sequencing were conducted 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 exhibited apical hypertrophic cardiomyopathy with a rare PLEC variant. The other three displayed left ventricular hypertrabeculation with poor compaction, deep recess formation, myocardial fibrosis, micronecrosis, and minimal inflammatory cell infiltration. The enrichment analysis indicated 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 morphologic and genetic evaluations improves the assessment of a sudden death risk in individuals with sQT.