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Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
  1. Benjamin D Solomon1,
  2. Kelly A Bear1,2,
  3. Adrian Wyllie1,
  4. Amelia A Keaton1,
  5. Christele Dubourg3,4,
  6. Veronique David3,4,
  7. Sandra Mercier4,5,
  8. Sylvie Odent4,5,
  9. Ute Hehr6,7,
  10. Aimee Paulussen8,
  11. Nancy J Clegg9,
  12. Mauricio R Delgado9,
  13. Sherri J Bale10,
  14. Felicitas Lacbawan11,
  15. Holly H Ardinger12,
  16. Arthur S Aylsworth13,14,
  17. Ntombenhle Louisa Bhengu15,
  18. Stephen Braddock16,
  19. Karen Brookhyser17,
  20. Barbara Burton18,
  21. Harald Gaspar19,
  22. Art Grix17,
  23. Dafne Horovitz20,
  24. Erin Kanetzke16,
  25. Hulya Kayserili21,
  26. Dorit Lev22,
  27. Sarah M Nikkel23,
  28. Mary Norton24,
  29. Richard Roberts25,
  30. Howard Saal26,
  31. G B Schaefer27,
  32. Adele Schneider28,
  33. Erika K Smith23,
  34. Ellen Sowry29,
  35. M Anne Spence30,
  36. Stavit A Shalev31,32,
  37. Carlos E Steiner33,
  38. Elizabeth M Thompson34,
  39. Thomas L Winder35,
  40. Joan Z Balog1,
  41. Donald W Hadley1,
  42. Nan Zhou1,
  43. Daniel E Pineda-Alvarez1,
  44. Erich Roessler1,
  45. Maximilian Muenke1
  1. 1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
  3. 3CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France
  4. 4CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France
  5. 5Service de genetique Clinique, CHU Hopital Sud, Rennes, France
  6. 6Center for Human Genetics, University of Regensburg, Regensburg, Germany
  7. 7Department of Human Genetics, University of Regensburg, Regensburg, Germany
  8. 8Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands
  9. 9Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  10. 10GeneDx, Gaithersburg, Maryland, USA
  11. 11Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
  12. 12Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA
  13. 13Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA
  14. 14Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
  15. 15Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa
  16. 16Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA
  17. 17Genetics Department, Kaiser Permanente, Sacramento, California, USA
  18. 18Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA
  19. 19Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
  20. 20Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil
  21. 21Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  22. 22Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
  23. 23Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  24. 24Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA
  25. 25Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA
  26. 26Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  27. 27Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  28. 28Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA
  29. 29Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
  30. 30Department of Pediatrics, University of California, Irvine, California, USA
  31. 31Genetics Institute, Emek Medical Center, Afula, Israel
  32. 32Rappaport faculty of Medicine, Technion, Haifa, Israel
  33. 33Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil
  34. 34Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia
  35. 35Prevention Genetics, Marshfield, Wisconsin, USA
  1. Correspondence to Dr Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA 20892; mamuenke{at}


Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences.

Objective To characterise genetic and clinical findings in individuals with SHH mutations.

Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases.

Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location.

Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

  • Holoprosencephaly
  • Sonic Hedgehog
  • SHH
  • genetics
  • genome-wide
  • academic medicine
  • adrenal disorders
  • anterior segment disease
  • cancer: breast
  • cancer: CNS
  • cytogenetics
  • molecular genetics
  • clinical genetics
  • developmental
  • diagnosis
  • guidelines
  • congenital heart disease
  • epigenetics
  • genetic screening/counselling
  • aneuploidy
  • chromosomal
  • ethics
  • complex traits
  • neurosciences

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  • BDS and KAB contributed equally to this work. The views expressed by KAB in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, nor the US government.

  • Funding This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by National Human Genome Research Institute IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All relevant data are included in this article. All other clinical information specific to patients is managed by their respective clinicians and/or our reference laboratories.