title: Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly.
abstract: BACKGROUND
  Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly.
  
  
  OBJECTIVE
  To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations.
  
  
  METHODS
  Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software).
  
  
  RESULTS
  112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations.
  
  
  CONCLUSIONS
  Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients.
  
  
  BACKGROUND
  98-HG-0249/04-HG-0093.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Bear
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Division of Medical Genomics, Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Sonir
authors.initials: S
authors.lastname: Antonini
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Marcela M
authors.initials: MM
authors.lastname: França
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erica H
authors.initials: EH
authors.lastname: Gerkes
authors.affiliation: Washington University Schl Mdcn, St. Louis, Missouri, USA.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Hadley
authors.affiliation: Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jarmo
authors.initials: J
authors.lastname: Jääskeläinen
authors.affiliation: Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Sabrina S
authors.initials: SS
authors.lastname: Paulo
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rump
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: SA Pathology, South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.affiliation: Department of Pediatrics, Clinical Genetics, Naval Medical Center, San Diego, California, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Willis
authors.affiliation: Prevention Genetics, Marshfield, Wisconsin, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Winder
authors.affiliation: Unidade de Endocrinologia Genética, LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D005145:Face / Q000473:pathology; D005385:Fingers / Q000473:pathology; D016142:Holoprosencephaly; D006801:Humans; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D014034:Toes / Q000473:pathology; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2
keywords: GLI2; Holoprosencephaly; Hypopituitarism; Pituitary abnormalities; Polydactyly
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