New insights into genotype–phenotype correlation for GLI3 mutations

• DOI: 10.1038/ejhg.2014.62
• Publication Date: 2014-04-16T11:39:53Z
• Authors: Florence Démurger; Amale Ichkou; Soumaya Mougou-Ze...; Martine Le Merrer; Géraldine Goudefroye; Anne-Lise Delezoide; Chloé Quélin; Sylvie Manouvrier; Geneviève Baujat; Mélanie Fradin; Laurent Pasquier; André Megarbané; Laurence Faivre; Clarisse Baumann; Sheela Nampoothiri; Joëlle Roume; Bertrand Isidor; Didier Lacombe; Marie-Ange Delrue; Sandra Mercier; Nicole Philip; Elise Schaefer; Muriel Holder; Amanda Krause; Fanny Laffargue; Martine Sinico; Daniel Amram; Gwenaelle André; Alain Liquier; Massimiliano Rossi; Jeanne Amiel; Fabienne Giuliano; Odile Boute; Anne Dieux-Coeslier; Marie-Line Jacque...; Alexandra Afenjar; Lionel Van Maldergem; Marylin Lackmy-Po...; Catherine Vincent...; Marie-Liesse Chauvet; Valérie Cormier-D...; Louise Devisme; David Geneviève; Arnold Munnich; Géraldine Viot; Odile Raoul; Serge Romana; Marie Gonzales; Ferechte Encha-Ra...; Sylvie Odent; Michel Vekemans; Tania Attie-Bitach
• Keywords: Gene Rearrangement; 0301 basic medicine; [SDV.GEN]Life Sciences [q-bio]/Genetics; DNA Mutational Analysis; Kruppel-Like Transcription Factors; Gene Expression; Nerve Tissue Proteins; [SDV.GEN] Life Sciences [q-bio]/Genetics; Haploinsufficiency; Acrocephalosyndactylia; 3. Good health; Cohort Studies; 03 medical and health sciences; Phenotype; Zinc Finger Protein Gli3; Mutation; Humans; Abnormalities, Multiple; Family; Genetic Association Studies; In Situ Hybridization, Fluorescence

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.