Mutations in ZIC2 in human holoprosencephaly: description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals

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.