HPE is deemed by most researchers to be caused by the genetic loss or mutational dysfunctions of minimal critical regions and relatively rare cytogenetic rearrangements that serve as core genetic susceptibility factors for humans in different risk factor genes at each key locus: SHH at 7q36, SIX3 at 2p21, ZIC2 at 13q3.2, and TGIF at 18p11.3 [15]. This evidence concerns the gene SIX3 and holoprosencephaly.