Mutations in ZIC2 in human holoprosencephaly: Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals

Benjamin D. Solomon, Felicitas Lacbawan, Sandra Mercier, Nancy J. Clegg, Mauricio R. Delgado, Kenneth Rosenbaum, Christèle Dubourg, Veronique David, Ann Haskins Olney, Lars Erik Wehner, Ute Hehr, Sherri Bale, Aimee Paulussen, Hubert J. Smeets, Emily Hardisty, Anna Tylki-Szymanska, Ewa Pronicka, Michelle Clemens, Elizabeth McPherson, Raoul C.M. HennekamJin Hahn, Elaine Stashinko, Eric Levey, Dagmar Wieczorek, Elizabeth Roeder, Chayim Can Schell-Apacik, Carol W. Booth, Ronald L. Thomas, Sue Kenwrick, Derek A.T. Cummings, Sophia M. Bous, Amelia Keaton, Joan Z. Balog, Donald Hadley, Nan Zhou, Robert Long, Jorge I. Vélez, Daniel E. Pineda-Alvarez, Sylvie Odent, Erich Roessler, Maximilian Muenke

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalJournal of medical genetics
Issue number8
StatePublished - Aug 2010

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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