New insights into genotype-phenotype correlation for GLI3 mutations

• Published in: European journal of human genetics : EJHG Vol. 23; no. 1; pp. 92 - 102
• Main Authors: Démurger, Florence, Ichkou, Amale, Mougou-Zerelli, Soumaya, Le Merrer, Martine, Goudefroye, Géraldine, Delezoide, Anne-Lise, Quélin, Chloé, Manouvrier, Sylvie, Baujat, Geneviève, Fradin, Mélanie, Pasquier, Laurent, Megarbané, André, Faivre, Laurence, Baumann, Clarisse, Nampoothiri, Sheela, Roume, Joëlle, Isidor, Bertrand, Lacombe, Didier, Delrue, Marie-Ange, Mercier, Sandra, Philip, Nicole, Schaefer, Elise, Holder, Muriel, Krause, Amanda, Laffargue, Fanny, Sinico, Martine, Amram, Daniel, André, Gwenaelle, Liquier, Alain, Rossi, Massimiliano, Amiel, Jeanne, Giuliano, Fabienne, Boute, Odile, Dieux-Coeslier, Anne, Jacquemont, Marie-Line, Afenjar, Alexandra, Van Maldergem, Lionel, Lackmy-Port-Lis, Marylin, Vincent-Delorme, Catherine, Chauvet, Marie-Liesse, Cormier-Daire, Valérie, Devisme, Louise, Geneviève, David, Munnich, Arnold, Viot, Géraldine, Raoul, Odile, Romana, Serge, Gonzales, Marie, Encha-Razavi, Ferechte, Odent, Sylvie, Vekemans, Michel, Attie-Bitach, Tania
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2015
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Acrocephalosyndactylia - diagnosis; Acrocephalosyndactylia - genetics; Clonal deletion; Cohort Studies; Corpus callosum; DNA Mutational Analysis; Epiglottis; Family; Fetuses; Gene deletion; Gene Expression; Gene Rearrangement; Genetic Association Studies; Genetics; Genotypes; Gli3 protein; Greig cephalopolysyndactyly syndrome; Haploinsufficiency; Humans; Hypothalamus; In Situ Hybridization, Fluorescence; Kruppel-Like Transcription Factors - genetics; Lethality; Life Sciences; Mutation; Neoplasia; Nerve Tissue Proteins - genetics; Phenotype; Phenotypes; Polydactyly; Proteins; Zinc Finger Protein Gli3; France
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2014.62

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.