The severity of HPE does increase with the loss of combined alleles; Gas1−/−; Cdon−/− mutants have a severe form of alobar HPE, which includes fusion of the nasal processes and absence of maxillary and mandibular skeletal elements (Fig. 3M–O) (Allen et al., 2007), whilst Cdon−/−; Boc−/− mice on a Cdon-resistant background have lobar HPE with more severe craniofacial abnormalities (Zhang et al., 2011). This evidence concerns the gene CDON and holoprosencephaly.