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 characterize genetic and clinical findings in patients with ZIC2 mutations.
Methods: Through the NIH and collaborating centers, DNA from approximately 1200 individuals with HPE-spectrum disorders was analyzed for sequence variations in ZIC2. We examined clinical details and included all other known cases of mutations in ZIC2 through a literature search.
Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, we find ZIC2 mutations in 8.4% (49/582) of probands. We describe a total of 157 individuals from 119 unrelated kindreds, 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. Further, we present evidence 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 counseling and diagnostic strategies.
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