New insights into genotype–phenotype correlation for GLI3 mutations

Abstract

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

“…20,22 In particular, the observed different impact of the two missense variants on SUFU subcellular distribution and degradation, GLI3 cleavage, and expression of target genes may enlighten some differences between the two families, such as the occurrence, in family COR369, of more severe polydactyly and of asymmetric polymicrogyria, prevalent in the perisylvian regions. Polymicrogyria has been occasionally reported in subjects with JS caused by pathogenic variants in distinct ciliary genes, 18,53,54 as well as in a boy with schizencephaly and partial absence of the corpus callosum carrying a SHH heterozygous variant.…”

“…[16][17][18][19] Similarly, heterozygous pathogenic variants directly affecting several members of the SHH pathway, including SHH itself (MIM: 600725), PTCH1, SMO (MIM: 601500), GLI2 (MIM: 165230), or GLI3 (MIM: 165240), result in a spectrum of autosomal-dominant developmental disorders including holoprosencephaly (MIM: 142945), schizencephaly with polymicrogyria (MIM: 269160), Curry-Jones syndrome (CJS [MIM: 601707]), Greig cephalopolysyndactyly syndrome (GCPS [MIM: 175700]), Pallister-Hall syndrome (MIM: 146510), and non-syndromic polydactylies (MIM: 174200, 174700), that are variably characterized by anomalies of the brain, midline face, and/or limbs. [20][21][22][23] An aberrant activity of the SHH pathway has also been firmly associated with increased risk of developing cancer. Germline heterozygous loss-of-function variants of either PTCH1 or SUFU (MIM: 607035) may cause a complex condition termed nevoid-basal-cell carcinoma syndrome (Gorlin syndrome [MIM: 109400]), characterized by the occurrence of several basal cell carcinomas and other cancers at a young age (<20 years), variably associated with developmental and skeletal abnormalities.…”

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas

“…By this missense mutation, an amino acid property is changed from hydrophobic (Proline, P) to hydrophilic (Serine, S) within the proteolytic cleavage (PC) site of GLI3 (blue arrow in upper panel). Typical location of pathogenic variants of GLI3 gene for GCPS (green bar) and PHS (red bar) are illustrated according to the report by Demurger F et al [19] …”

“…Since a delicate balance between the functioning activator and repressor is essential for proper development [2,17,18], the simple location of the pathogenic variants in GLI3 site does not always clearly correlate with the clinical manifestations [19]. Also, some pathogenic variants cause overlapping phenotypes of GCPS and PHS [19]. Therefore, the concept of GLI3 morphopathies has been postulated to designate these mutually overlapped syndromes [5].…”

“…PHS, on the other hand, shows a lethal condition involving hypothalamic dysfunction, skeletal limb defects, craniofacial and urogenital malformation attributed to pathogenic variants of GLI3 gene, typically within or around the PC domain of the GLI3 protein, resulting in a relative reduction in the functioning of the GLI3 repressor form [16]. Since a delicate balance between the functioning activator and repressor is essential for proper development [2,17,18], the simple location of the pathogenic variants in GLI3 site does not always clearly correlate with the clinical manifestations [19]. Also, some pathogenic variants cause overlapping phenotypes of GCPS and PHS [19].…”