Consequently, pathogenic variants in genes encoding Shh signaling components such as Smoothened (loss of function/haploinsufficiency) or Patched (gain of function) are associated with catastrophic midline defect phenotypes including holoprosencephaly (HPE), craniofacial defects (3, 5), and disorders of eye development (4, 6). This evidence concerns the gene SHH and holoprosencephaly.