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Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly
  1. Kelly A Bear1,2,
  2. Benjamin D Solomon1,3,4,
  3. Sonir Antonini5,
  4. Ivo J P Arnhold6,
  5. Marcela M França6,
  6. Erica H Gerkes7,
  7. Dorothy K Grange8,
  8. Donald W Hadley1,
  9. Jarmo Jääskeläinen9,
  10. Sabrina S Paulo5,
  11. Patrick Rump7,
  12. Constantine A Stratakis10,
  13. Elizabeth M Thompson11,12,
  14. Mary Willis13,
  15. Thomas L Winder14,
  16. Alexander A L Jorge15,
  17. Erich Roessler1,
  18. Maximilian Muenke1
  1. 1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii, USA
  3. 3Division of Medical Genomics, Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA
  4. 4Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA
  5. 5Department of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
  6. 6Unidade 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
  7. 7Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  8. 8Washington University Schl Mdcn, St. Louis, Missouri, USA
  9. 9Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  10. 10Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  11. 11SA Pathology, South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, South Australia, Australia
  12. 12Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia
  13. 13Department of Pediatrics, Clinical Genetics, Naval Medical Center, San Diego, California, USA
  14. 14Prevention Genetics, Marshfield, Wisconsin, USA
  15. 15Unidade de Endocrinologia Genética, LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  1. Correspondence to Dr Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, 35 Convent Drive, Building 35, Room 1B-203, Bethesda, MD 20892-3717, USA; mamuenke{at}


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.

Trial registration 98-HG-0249/04-HG-0093.

  • Holoprosencephaly
  • GLI2
  • Polydactyly
  • Pituitary abnormalities
  • Hypopituitarism

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