RT Journal Article
SR Electronic
T1 Mutations in <em>ZIC2</em> in human holoprosencephaly: description of a Novel <em>ZIC2</em> specific phenotype and comprehensive analysis of 157 individuals
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 513
OP 524
DO 10.1136/jmg.2009.073049
VO 47
IS 8
A1 Benjamin D Solomon
A1 Felicitas Lacbawan
A1 Sandra Mercier
A1 Nancy J Clegg
A1 Mauricio R Delgado
A1 Kenneth Rosenbaum
A1 Christèle Dubourg
A1 Veronique David
A1 Ann Haskins Olney
A1 Lars-Erik Wehner
A1 Ute Hehr
A1 Sherri Bale
A1 Aimee Paulussen
A1 Hubert J Smeets
A1 Emily Hardisty
A1 Anna Tylki-Szymanska
A1 Ewa Pronicka
A1 Michelle Clemens
A1 Elizabeth McPherson
A1 Raoul C M Hennekam
A1 Jin Hahn
A1 Elaine Stashinko
A1 Eric Levey
A1 Dagmar Wieczorek
A1 Elizabeth Roeder
A1 Chayim Can Schell-Apacik
A1 Carol W Booth
A1 Ronald L Thomas
A1 Sue Kenwrick
A1 Derek A T Cummings
A1 Sophia M Bous
A1 Amelia Keaton
A1 Joan Z Balog
A1 Donald Hadley
A1 Nan Zhou
A1 Robert Long
A1 Jorge I Vélez
A1 Daniel E Pineda-Alvarez
A1 Sylvie Odent
A1 Erich Roessler
A1 Maximilian Muenke
YR 2010
UL http://jmg.bmj.com/content/47/8/513.abstract
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.