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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 Lacbawan2,
  3. Sandra Mercier3,
  4. Nancy J Clegg4,
  5. Mauricio R Delgado4,
  6. Kenneth Rosenbaum5,
  7. Christele Dubourg3,
  8. Veronique David3,
  9. Ann Haskins Olney6,
  10. Lars-Erik Wehner7,
  11. Ute Hehr8,
  12. Sherri Bale9,
  13. Aimee Paulussen10,
  14. Hubert J Smeets11,
  15. Emily Hardisty12,
  16. Anna Tylki-Szymanska13,
  17. Ewa Pronicka13,
  18. Michelle Clemens14,
  19. Elizabeth McPherson15,
  20. Raoul C.M. Hennekam16,
  21. Jin Hahn17,
  22. Elaine Stashinko18,
  23. Eric Levey18,
  24. Dagmar Wieczorek19,
  25. Elizabeth Roeder20,
  26. Chayim Can Schell-Apacik21,
  27. Carol W Booth22,
  28. Ronald L Thomas23,
  29. Sue Kenwrick24,
  30. Amelia Keaton1,
  31. Joan Z Balog1,
  32. Donald Hadley1,
  33. Nan Zhou1,
  34. Robert Long1,
  35. Jorge I Velez1,
  36. Daniel E Pineda-Alvarez1,
  37. Sylvie Odent3,
  38. Erich Roessler1,
  39. Maximilian Muenke1,*
  1. 1 NHGRI, United States;
  2. 2 NHGRI, SUNY-Downstate, United States;
  3. 3 Universite de Rennes, France;
  4. 4 University of Texas SW Medical Center, United States;
  5. 5 Children's National Medical Center, United States;
  6. 6 University of Nebraska Medical Center, United States;
  7. 7 Practice of Human Genetics, Germany;
  8. 8 University of Regensburg, Germany;
  9. 9 GeneDx, United States;
  10. 10 Maastricht University, Netherlands;
  11. 11 University of Maastricht, Netherlands;
  12. 12 University of North Carolina-Chapel Hill, United States;
  13. 13 The Children's Memorial Health Institute, Poland;
  14. 14 University of Pittsburgh Medical Center, United States;
  15. 15 Marshfield Clinic, United States;
  16. 16 Ormond Street Hospital for Children, United Kingdom;
  17. 17 Stanford University, United States;
  18. 18 Johns Hopkins University, United States;
  19. 19 University Duisburg-Essen, Germany;
  20. 20 University of Texas Health Science Center at San Antonio, United States;
  21. 21 University of Munich, University of Berlin, Germany;
  22. 22 Lutheran General Hospital, United States;
  23. 23 Drexel University, United States;
  24. 24 Addenbrooke's Hospital, United Kingdom
  1. Correspondence to: Maximilian Muenke, Medical Genetics Branch, NHGRI/NIH, 35 Convent Drive, Bldg 35, Room 1B203, MSC 3717, Bethesda, 20892-3717, United States; mamuenke{at}mail.nih.gov

Abstract

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 characterize genetic and clinical findings in patients with ZIC2 mutations.

Methods: Through the NIH and collaborating centers, DNA from approximately 1200 individuals with HPE-spectrum disorders was analyzed for sequence variations in ZIC2. We examined clinical details and included all other known cases of mutations in ZIC2 through a literature search.

Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, we find ZIC2 mutations in 8.4% (49/582) of probands. We describe a total of 157 individuals from 119 unrelated kindreds, 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. Further, we present evidence 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 counseling and diagnostic strategies.

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