Dataset Information

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.

SUBMITTER: Demurger F

PROVIDER: S-EPMC4266745 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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New insights into genotype-phenotype correlation for GLI3 mutations.

Démurger Florence F Ichkou Amale A Mougou-Zerelli Soumaya S Le Merrer Martine M Goudefroye Géraldine G Delezoide Anne-Lise AL Quélin Chloé C Manouvrier Sylvie S Baujat Geneviève G Fradin Mélanie M Pasquier Laurent L Megarbané André A Faivre Laurence L Baumann Clarisse C Nampoothiri Sheela S Roume Joëlle J Isidor Bertrand B Lacombe Didier D Delrue Marie-Ange MA Mercier Sandra S Philip Nicole N Schaefer Elise E Holder Muriel M Krause Amanda A Laffargue Fanny F Sinico Martine M Amram Daniel D André Gwenaelle G Liquier Alain A Rossi Massimiliano M Amiel Jeanne J Giuliano Fabienne F Boute Odile O Dieux-Coeslier Anne A Jacquemont Marie-Line ML Afenjar Alexandra A Van Maldergem Lionel L Lackmy-Port-Lis Marylin M Vincent-Delorme Catherine C Chauvet Marie-Liesse ML Cormier-Daire Valérie V Devisme Louise L Geneviève David D Munnich Arnold A Viot Géraldine G Raoul Odile O Romana Serge S Gonzales Marie M Encha-Razavi Ferechte F Odent Sylvie S Vekemans Michel M Attie-Bitach Tania T

European journal of human genetics : EJHG 20140416 1

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 t ...[more]

PMID: 24736735

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Project description:Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-? signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (?(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Dataset Information

New insights into genotype-phenotype correlation for GLI3 mutations.

Publications

New insights into genotype-phenotype correlation for GLI3 mutations.

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