Our data support the concept that WFS1 and WFS2 constitute a continuous clinical spectrum with overlapping phenotypes, and although CISD2 mutations are relatively rare, this gene should be screened in patients manifesting the defining features of WS, in particular early-onset diabetes mellitus and optic atrophy, but in whom no pathogenic WFS1 mutations have been conclusively identified. Here, CISD2 is linked to Leber hereditary optic neuropathy.