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Mutations in ZIC2 in human holoprosencephaly: description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals
Journal article   Open access   Peer reviewed

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, Christele Dubourg, Veronique David, Ann Haskins Olney, Lars-Erik Wehner, …
Journal of medical genetics, v 47(8), pp 513-524
01 Aug 2010
DOI: https://doi.org/10.1136/jmg.2009.073049
PMID: 19955556
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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http://dare.uva.nl/personal/pure/en/publications/mutations-in-zic2-in-human-holoprosencephaly-description-of-a-novel-zic2-specific-phenotype-and-comprehensive-analysis-of-157-individuals(18c40781-fece-4942-b9b5-c63424c52650).htmlView
Published, Version of Record (VoR)Open Access (License Unspecified),  Open
url
https://doi.org/10.1136/jmg.2009.073049View
Published, Version of Record (VoR) Open

Abstract

Genetics & Heredity Life Sciences & Biomedicine Science & Technology
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.

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Genetics & Heredity
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