Exome sequencing of an Indian hypertrophic cardiomyopathy (HCM) cohort uncovered six heterozygous missense variants — AKT1 (p.G37V), mTOR (p.A152S, p.D297N, p.R1818H), and RICTOR (p.R241Q, p.T1209M) — in unrelated patients who lacked known sarcomeric mutations. All six variants were novel or ultra-rare and classified likely pathogenic under ACMG criteria. In cardiomyocyte cell models, each mutant protein produced significantly enlarged cell surface area, elevated mTOR signaling, hypertrophic marker gene expression, and increased global protein synthesis, consistent with gain-of-function mechanics.
HCM affects roughly 1 in 500 adults globally, yet a meaningful fraction carry no identifiable sarcomeric mutation, leaving families without actionable genetic counseling. This work extends a prior finding by the same group linking RPS6KB1 — another AKT pathway node — to HCM, building a coherent mechanistic picture: hyperactivated mTORC2/AKT/mTORC1 signaling drives pathological cardiac growth independent of sarcomeric dysfunction. The Indian-specific cohort is clinically important because South Asian populations are underrepresented in cardiovascular genomics databases, making variant interpretation difficult. Practically, identifying gain-of-function mTOR variants opens a therapeutic hypothesis: rapalogs and AKT inhibitors already in clinical use for oncology could theoretically be repurposed — though cardiac-specific safety data would be required. Limitations are notable: the cohort size is small, functional validation is cell-based rather than in vivo, and causal proof in humans is absent. As a preprint not yet peer-reviewed, these findings must be considered preliminary until independent replication and expert scrutiny confirm them. Still, the mechanistic consistency across all six variants makes this more than incremental.