Significance The large superfamily of cadherins serve essential roles in cell–cell interactions and guidance. The extracellular cadherin (EC) domains responsible for the biological functions are decorated with O-linked mannose glycans, but the functions of these O-glycans are poorly understood. Here we describe an O-mannosylation pathway orchestrated by four homologous TMTC1–4 genes that is dedicated selectively to the cadherin superfamily. Mutations in the TMTC3 gene cause cobblestone lissencephaly, demonstrating the importance of this type of O-mannosylation.