Recent advances in the diagnosis and molecular pathogenesis of holoprosencephaly: a review

Holoprosencephaly (HPE) is the most common structural anomaly of developing forebrain, characterized by incomplete separation of the cerebral hemispheres. While mutations in the Sonic Hedgehog (SHH) signaling pathway remain the most established genetic cause, recent studies have identified an expanding list of genes and molecular networks involved in the pathogenesis of HPE. These include modulators of the NODAL, NOTCH, WNT/PCP, FGF, and RAS/ERK1/2 pathways as well as components of ciliary structures and cohesin complexes. Incomplete penetrance, broad phenotypic heterogeneity, and gene-environment interactions complicate diagnostic and counselling efforts. This review summarizes recent insights into the molecular mechanisms of HPE, highlighting key signalling networks, gene candidates, and phenotypic correlations. We also discuss under-recognised contributors such as cohesin and ciliary gene defects, which may account for a significant subset of unresolved cases. Finally, we propose a diagnostic framework incorporating clinical stratification, extended gene panels, and consideration of syndromic features.