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Mutations in ZIC2 in human holoprosencephaly: description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals
  1. Benjamin D Solomon1,
  2. Felicitas Lacbawan1,2,
  3. Sandra Mercier3,4,
  4. Nancy J Clegg5,
  5. Mauricio R Delgado5,
  6. Kenneth Rosenbaum6,
  7. Christèle Dubourg3,
  8. Veronique David3,
  9. Ann Haskins Olney7,
  10. Lars-Erik Wehner8,
  11. Ute Hehr9,
  12. Sherri Bale10,
  13. Aimee Paulussen11,
  14. Hubert J Smeets11,12,
  15. Emily Hardisty13,
  16. Anna Tylki-Szymanska14,
  17. Ewa Pronicka14,
  18. Michelle Clemens15,
  19. Elizabeth McPherson16,
  20. Raoul C M Hennekam17,18,
  21. Jin Hahn19,
  22. Elaine Stashinko20,
  23. Eric Levey20,
  24. Dagmar Wieczorek21,
  25. Elizabeth Roeder22,
  26. Chayim Can Schell-Apacik23,24,
  27. Carol W Booth25,
  28. Ronald L Thomas26,
  29. Sue Kenwrick27,
  30. Derek A T Cummings28,
  31. Sophia M Bous1,
  32. Amelia Keaton1,
  33. Joan Z Balog1,
  34. Donald Hadley1,
  35. Nan Zhou1,
  36. Robert Long1,
  37. Jorge I Vélez1,
  38. Daniel E Pineda-Alvarez1,
  39. Sylvie Odent3,4,
  40. Erich Roessler1,
  41. Maximilian Muenke1
  1. 1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Department of Pathology, State University of New York-Downstate Medical Center, Brooklyn, New York, USA
  3. 3CNRS Génétique et Développement, Université de Rennes, 35043 Rennes Cedex, France
  4. 4Service de génétique clinique, CHU Hôpital Sud, 35043 Rennes Cedex, France
  5. 5Department of Neurology, Texas Scottish Rite Hospital for Children, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  6. 6Department of Genetics, Children's National Medical Center, Washington, DC, USA
  7. 7Department of Medical Genetics, Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, USA
  8. 8Practice of Human Genetics, Linden, Germany
  9. 9Center for and Department of Human Genetics, University of Regensburg, Regensburg, Germany
  10. 10GeneDx, Gaithersburg, Maryland, USA
  11. 11Department of Clinical Genetics, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
  12. 12GROW, School for Oncology and Developmental Biology, MUMC+, Maastricht, The Netherlands
  13. 13Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  14. 14Clinic of Metabolic Diseases, Endocrinology and Diabetology, The Children's Memorial Health Institute, Warsaw, Poland
  15. 15Department of Genetics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  16. 16Department of Genetics, Marshfield Clinic, Marshfield, Wisconsin, USA
  17. 17Clinical and Molecular Genetics Unit, Institute of Child Health, Great Ormond Street Hospital for Children, UCL, London, UK
  18. 18Department of Pediatrics, Academic Medical Center, Amsterdam, Netherlands
  19. 19Department of Neurology, Stanford University School of Medicine, Palo Alto, California, USA
  20. 20Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA
  21. 21Institute of Human Genetics, University Duisburg-Essen, Essen, Germany
  22. 22Department of Pediatrics, Division of Genetics and Metabolic Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  23. 23Institute of Social Pediatric and Adolescent Medicine of the University of Munich, Munich, Germany
  24. 24Practice of Human Genetics, Berlin, Germany
  25. 25Department of Genetics, Lutheran General Hospital, Park Ridge, Illinois, USA
  26. 26Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
  27. 27Clinical Genetics, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, UK
  28. 28Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  1. Correspondence to Maximilian Muenke, National Institutes of Health, Building 35, Room 1B-203, Bethesda, MD 20892, USA; mamuenke{at}


Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE.

Objective To characterise genetic and clinical findings in patients with ZIC2 mutations.

Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search.

Results By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears.

Conclusions HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

  • Holoprosencephaly
  • HPE
  • ZIC2

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  • BDS and FL authors contributed equally.

  • Funding This research was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, United States of America and GIS Maladies Rares GISMR0701/DHOS, France. Other Funders: NIH; Howard Hughes Medical Institute.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

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