In this study, we identified RPs as novel candidate genetic regulators of hypoplastic phenotypes observed in HLHS, as (1) rare, predicted-damaging variants affecting RP genes are enriched in HLHS probands as compared to healthy controls, (2) KD of most RPs impairs proliferation in hiPSC-CMs (59/80 tested) and heart development in flies (6/6 tested), and (3) systemic loss of rps15A function causes heart-specific hypoplastic phenotypes in zebrafish. This evidence concerns the gene RPS15A and hypoplastic left heart syndrome.