Mutations in genes encoding HIF pathway components cause familial ECYT. A gain-of-function (GoF) mutation in the EPO or EPOR gene causes isolated ECYT, whereas a loss-of-function (LoF) mutation in the EGLN1, EGLN2, or VHL gene or a GoF mutation in the EPAS1 gene causes ECYT as part of a syndrome resulting from global dysregulation of the HIF pathway.