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 an oligogenic disease having multiple inheritance modes. Among them, oligogenic inheritance would require two or more events involving genes from the same or different signaling pathways with functional relationship. This oligogenic 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.

GLI2 is a mediator of SHH action. Roessler et al. (2003, 2005) isolated the human GLI2 gene and searched for mutations in 390 patients who met clinical criteria for HPE. Very few patients had GLI2 mutations that, in addition to HPE, were noted to have polydactyly, midfacial and/or pituitary abnormalities. The authors observed an autosomal dominant inheritance with incomplete penetrance and inferred that pituitary and facial structures were more sensitive to a reduction in GLI2 activity than the ventral forebrain was. Subsequently, Rahimov et al. (2006) screened GLI2 in patients with isolated midfacial defects, and França et al. (2010) screened patients with isolated pituitary hormone deficiency without HPE. A comprehensive review of GLI2 mutations also in subjects without hypopituitarism that included patients with HPE and/or midfacial defects or their normal relatives has been published by Bear et al. (2014).

Larger deletions of chromosome 2q, including GLI2 and several additional genes, have been described. Kevelam et al. (2012) reported a heterozygous submicroscopic 1.3 kb deletion of 2q14.2 in a patient with a cleft lip and palate and panhypopituitarism. Gustavsson et al. (2006) described a balanced translocation and a submicroscopic deletion of 2q14.2–2q22.1 that included 42 known genes in addition to GLI2 with a complex phenotype that included, among others, polydactyly, GH deficiency, hypospadias and undescended testes.
A mutant zebrafish with loss-of-function gli2 (yoo-too, yot) was shown to have anterior pituitary hypoplasia and abnormal patterning of the ventral central nervous system.

In human patients, truncating mutations may be identified along the length of the GLI2 gene and there is no evidence for correlation between the location of these truncating mutations relative to known functional domains and the patient phenotype. As the activation domain is located at the distal portion of the molecule, all mutations leading to truncation would be expected to behave similarly on a functional level. So pathogenic mutations in GLI2 are suspected to result in a loss of function (haploinsufficiency).