AKT1/mTOR/RICTOR risk variants in Indian hypertrophic cardiomyopathy patients

Hypertrophic cardiomyopathy is a hereditary heart muscle disease characterized by abnormal ventricular thickening and is predominantly caused by mutations in sarcomeric and signaling genes. Despite these advances, a substantial proportion of patients carry no identifiable pathogenic variants in these genes. Recently, we have shown that mutations in the RPS6KB1 gene (a member of the Akt signaling pathway) can lead to HCM. However, the genetic role of other members of the AKT pathway remains unknown in HCM. To address this gap, we used exome sequencing of an Indian-specific HCM patient cohort and identified six heterozygous missense variants in unrelated patients, including AKT1 (p.G37V), mTOR (p.A152S, p.D297N, p.R1818H), and RICTOR (p.R241Q, p.T1209M). The identified variants were either novel or ultra-rare and were classified as likely pathogenic according to ACMG guidelines. Functional consequences were evaluated using AKT1, mTOR, and RICTOR mutant proteins and compared with wild-type in a cardiomyocyte cell model. All six mutated proteins showed a significant increase in cell surface area, elevated mTOR signaling, induction of hypertrophic marker gene expression, and enhanced global protein synthesis, suggesting a gain-of-function effect. These findings underscore a potential genetic risk associated with the AKT/mTOR/RICTOR axis in patients with HCM.