PT  - JOURNAL ARTICLE
AU  - Solomon, Benjamin D
AU  - Lacbawan, Felicitas
AU  - Mercier, Sandra
AU  - Clegg, Nancy J
AU  - Delgado, Mauricio R
AU  - Rosenbaum, Kenneth
AU  - Dubourg, Christèle
AU  - David, Veronique
AU  - Olney, Ann Haskins
AU  - Wehner, Lars-Erik
AU  - Hehr, Ute
AU  - Bale, Sherri
AU  - Paulussen, Aimee
AU  - Smeets, Hubert J
AU  - Hardisty, Emily
AU  - Tylki-Szymanska, Anna
AU  - Pronicka, Ewa
AU  - Clemens, Michelle
AU  - McPherson, Elizabeth
AU  - Hennekam, Raoul C M
AU  - Hahn, Jin
AU  - Stashinko, Elaine
AU  - Levey, Eric
AU  - Wieczorek, Dagmar
AU  - Roeder, Elizabeth
AU  - Schell-Apacik, Chayim Can
AU  - Booth, Carol W
AU  - Thomas, Ronald L
AU  - Kenwrick, Sue
AU  - Cummings, Derek A T
AU  - Bous, Sophia M
AU  - Keaton, Amelia
AU  - Balog, Joan Z
AU  - Hadley, Donald
AU  - Zhou, Nan
AU  - Long, Robert
AU  - Vélez, Jorge I
AU  - Pineda-Alvarez, Daniel E
AU  - Odent, Sylvie
AU  - Roessler, Erich
AU  - Muenke, Maximilian
TI  - Mutations in <em>ZIC2</em> in human holoprosencephaly: description of a Novel <em>ZIC2</em> specific phenotype and comprehensive analysis of 157 individuals
AID  - 10.1136/jmg.2009.073049
DP  - 2010 Aug 01
TA  - Journal of Medical Genetics
PG  - 513--524
VI  - 47
IP  - 8
4099  - http://jmg.bmj.com/content/47/8/513.short
4100  - http://jmg.bmj.com/content/47/8/513.full
SO  - J Med Genet2010 Aug 01; 47
AB  - 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.