TY - JOUR 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 SP - 513 LP - 524 DO - 10.1136/jmg.2009.073049 VL - 47 IS - 8 AU - Benjamin D Solomon AU - Felicitas Lacbawan AU - Sandra Mercier AU - Nancy J Clegg AU - Mauricio R Delgado AU - Kenneth Rosenbaum AU - Christèle Dubourg AU - Veronique David AU - Ann Haskins Olney AU - Lars-Erik Wehner AU - Ute Hehr AU - Sherri Bale AU - Aimee Paulussen AU - Hubert J Smeets AU - Emily Hardisty AU - Anna Tylki-Szymanska AU - Ewa Pronicka AU - Michelle Clemens AU - Elizabeth McPherson AU - Raoul C M Hennekam AU - Jin Hahn AU - Elaine Stashinko AU - Eric Levey AU - Dagmar Wieczorek AU - Elizabeth Roeder AU - Chayim Can Schell-Apacik AU - Carol W Booth AU - Ronald L Thomas AU - Sue Kenwrick AU - Derek A T Cummings AU - Sophia M Bous AU - Amelia Keaton AU - Joan Z Balog AU - Donald Hadley AU - Nan Zhou AU - Robert Long AU - Jorge I Vélez AU - Daniel E Pineda-Alvarez AU - Sylvie Odent AU - Erich Roessler AU - Maximilian Muenke Y1 - 2010/08/01 UR - http://jmg.bmj.com/content/47/8/513.abstract N2 - 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. ER -