KCNA2 variants cause dilated cardiomyopathy, obesity and sleep apnea through RAC-ERK pathway

Dilated cardiomyopathy (DCM) is a heart condition characterized by systolic and diastolic dysfunction. In many instances, patients with DCM coexist with obesity and sleep apnea. It is unclear whether genetic variants contribute to the combined phenotypes of DCM, obesity, and sleep apnea. Here, using next-generation sequencing, we identified pathogenic KCNA2 variants in patients of diverse ancestry with DCM, Obesity, and Sleep Apnea (termed DOSA). Electrophysiological and biochemical assays using biosensors revealed loss of membrane current due to trafficking defects in cells expressing KCNA2 variants. Furthermore, cellular models including patient-specific iPSC cardiomyocytes and organoid models displayed RAC1-ERK1/2 hyperactivation in disease pathogenesis. A Drosophila model expressing KCNA2 variant showed DOSA-like phenotypes which was rescued using RAC1 inhibitors. Our results provide the first evidence that KCNA2 variants can lead to DOSA phenotypes, further expanding the genetic regulatory roles of potassium channels in human diseases.