TLCD3B is a non-canonical ceramide synthase localized to the endoplasmic reticulum that catalyzes ceramide biosynthesis through sphingosine N-acyltransferase activity 1. The protein plays a critical role in maintaining proper ceramide homeostasis, particularly in photoreceptors, where it functions to preserve both retinal function and structure 2. Loss-of-function variants in TLCD3B cause cone-rod dystrophy 22, an inherited retinal dystrophy characterized by progressive photoreceptor degeneration 1. TLCD3B knockout mice exhibit significantly reduced cone photoreceptor light responses, outer nuclear layer thinning, and cone photoreceptor loss 1. Mechanistically, TLCD3B deficiency results in reduced levels of specific ceramide species (C16-, C18-, and C20-ceramides), and TLCD3B exhibits functional redundancy with canonical ceramide synthases in maintaining the overall ceramide profile rather than acting as a single entity 2. Gene therapy using subretinal AAV8-mediated TLCD3B delivery successfully rescues retinal degeneration in knockout mice, with photoreceptor-specific expression being sufficient for therapeutic benefit, confirming TLCD3B's essential role in photoreceptor survival 3. This represents the first identified pathogenic ceramide synthase variant associated with human retinal dystrophy, establishing a novel link between ceramide synthesis disruption and photoreceptor degeneration.