Molecular characteristics

To date, heterozygous mutations in 15 genes have been identified in HPE patients with four major genes (Sonic hedgehog or SHH, ZIC2, SIX3, TGIF1), and eleven genes that are considered as minor genes including GLI2 (MIM #165230; 2q14). These genes encode proteins playing a role in early brain development, which mostly belong to the signaling pathway SHH. 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.

As NGS technology became accessible, gene-panel sequencing method was performed and GLI2 was systematically studied, and now whole exome sequencing (WES) is routinely used to investigate novel HPE patients, in combination with comparative genomic hybridization (CGH) array.