New insights into genotype–phenotype correlation for GLI3 mutations

The phenotypic spectrum of GLI3mutations 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 atresiaand bifid epiglottis. Typical GCPS combines polysyndactylyof hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3mutations, highlighting the bifunctional nature of GLI3during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3gene (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 callosumobserved in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3mutations and extend the phenotypic spectrum of malformations such as agnathiaand reductional limbs defects. GLI3expression studied by in situ hybridization during human development confirms its early expression in target tissues.