Molecular Basis of Sarcomeric Variants and the Modifying Role of Non-sarcomeric Genes in Sudden Unexplained Nocturnal...

Sudden unexplained nocturnal death syndrome (SUNDS), a subtype of sudden unexplained death, predominantly affects young, otherwise healthy individuals, with a higher prevalence in male subjects and a geographic concentration in Southeast Asia, particularly Thailand. Despite extensive investigation, the genetic basis of SUNDS remains incompletely understood. Sarcomeric and non-sarcomeric gene variants were investigated in 98 SUNDS cases using whole-exome sequencing. Postmortem cardiac examination and molecular modeling were performed to assess myocardial abnormalities and the structural impact of selected sarcomeric variants. Eleven missense variants in five sarcomeric genes (MYBPC3, MYH7, TNNI3, TNNT2, and TPM1) were identified in 12 cases (12.2%), whereas 37 variants across 18 non-sarcomeric genes were detected in 29 cases (29.6%). The MYH7 variant c.1562T>C (p.Ile521Thr) was identified as likely pathogenic. Cardiac histopathology revealed heterogeneous myocardial remodeling, including myocyte hypertrophy and interstitial fibrosis; some MYH7 variant carriers displayed increased left ventricular wall thickness (>1.5 cm). Molecular modeling of the TPM1 variant c.641A>G (p.Tyr214Cys), located in the hinge region of the tropomyosin-troponin regulatory complex, suggested disruption of a native π-π stacking interaction, potentially affecting thin filament stability. Sarcomeric variants were associated with heterogeneous myocardial remodeling in SUNDS. These findings highlight the genetic and pathologic heterogeneity of SUNDS and suggest that sarcomeric gene variants represent a previously underrecognized contributor to myocardial remodeling and arrhythmogenic risk.