To date heterozygous mutations in 15 genes have been identified in HPE patients with four major genes including Sonic hedgehog or SHH (MIM# 600725; 7q36; HPE3), and eleven genes that are considered as minor genes (PTCH1, TDGF1, FOXH1, GLI2, DISP1, FGF8, GAS1, CDON, NODAL, DLL1 and recently STIL). These genes encode proteins playing a role in early brain development, which mostly belong to the signaling pathway Shh.
Mutations in SHH are inherited from an unaffected parent or parent harboring only a microform of HPE in 70% of the cases. It suggests that other events are necessary to develop the disease. Consequently, the mode of inheritance initially described as autosomal dominant with an incomplete penetrance and a variable expression has been redefined. HPE is now listed as a polygenic disease having multiple inheritance modes. Among them, polygenic inheritance would require two or more events involving genes from the same or different signaling pathways with functional relationship. This polygenic inheritance plays a role in the variability of the phenotype especially when there is a functional relationship between mutated genes, as this is the case for HPE genes.
Genetic analysis of HPE has for a long time relied on a Sanger sequencing approach. SHH was the first gene discovered and studied. As NGS technology became accessible, gene-panel sequencing method was performed, and now whole exome sequencing (WES) is now routinely used to investigate novel HPE patients, in combination with comparative genomic hybridization (CGH) array.