We show a potential role for RP function in cardiac development and HLHS pathogenesis as: (1) RPs are central regulators of CM proliferation; (2) RP variants are enriched in a cohort of poor-outcome HLHS patients; (3) a rare predicted-damaging promoter variant in RPS15A was associated with HLHS in familial CHD (75H); (4) KD of RPs in vivo results in cardiac deficiencies in hPSC-CMs, Drosophila, and zebrafish; and (5) induces TP53 signaling and blocks proliferation that can be alleviated by inhibition of TP53 in the vertebrate models. The gene discussed is TP53; the disease is hypoplastic left heart syndrome.