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Background  We have identified the cardiomyopathy‐susceptibility gene vinculin (  VCL  ) mutation M94I may account for a sudden unexplained nocturnal death syndrome ( SUNDS ) case. We addressed whether   VCL   common variant D841H is associated with  SUNDS .    Methods and Results  In 8 of 120  SUNDS  cases, we detected an East Asian common  VCL  variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with  SUNDS  victims (10 of 240) gives an odds ratio for  SUNDS  of 5.226 (95%  CI , 2.321, 11.769). The  VCL ‐D841H variant was engineered and either coexpressed with cardiac sodium channel ( SCN 5A) in  HEK 293 cells or overexpressed in human induced pluripotent stem‐cell–derived cardiomyocytes to examine its effects on sodium channel function using the whole‐cell patch‐clamp method. In  HEK 293 cells, under physiological  pH  conditions ( pH  7.4), D841H caused a 29% decrease in peak   I  N   a  amplitude compared to wild type ( WT ), whereas under acidotic conditions ( pH  7.0), D841H decreased further to 43% along with significant negative shift in inactivation compared to  WT  at  pH  7.4. In induced pluripotent stem‐cell‐derived cardiomyocytes, similar effects of D841H on   I  N   a  were observed.  VCL  colocalized with  SCN 5A at the intercalated disk in human cardiomyocytes.  VCL  was also confirmed to directly interact with  SCN 5A, and  VCL ‐D841H did not disrupt the association of  VCL  and SCN5A.    Conclusions  A  VCL  common variant was genetically and biophysically associated with Chinese  SUNDS . The aggravation of loss of function of SCN5A caused by  VCL ‐D841H under acidosis supports that nocturnal sleep respiratory disorders with acidosis may play a key role in the pathogenesis of  SUNDS .

An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population