GLI2 and holoprosencephaly: However, the findings presented here illustrate the ‘multiple hit’ hypothesis of complex disease and should prompt careful investigation of the etiological role of environmental Hh-pathway inhibitors in the context of predisposing mutations in genes such as Gli2. Building upon the study presented here, continued elucidation of the intricate gene-environment interactions that cause HPE provides a direct path to improving clinical management and developing effective prevention strategies.