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.
Solomon
Benjamin D
BD
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lacbawan
Felicitas
F
Mercier
Sandra
S
Clegg
Nancy J
NJ
Delgado
Mauricio R
MR
Rosenbaum
Kenneth
K
Dubourg
Christèle
C
David
Veronique
V
Olney
Ann Haskins
AH
Wehner
Lars-Erik
LE
Hehr
Ute
U
Bale
Sherri
S
Paulussen
Aimee
A
Smeets
Hubert J
HJ
Hardisty
Emily
E
Tylki-Szymanska
Anna
A
Pronicka
Ewa
E
Clemens
Michelle
M
McPherson
Elizabeth
E
Hennekam
Raoul C M
RC
Hahn
Jin
J
Stashinko
Elaine
E
Levey
Eric
E
Wieczorek
Dagmar
D
Roeder
Elizabeth
E
Schell-Apacik
Chayim Can
CC
Booth
Carol W
CW
Thomas
Ronald L
RL
Kenwrick
Sue
S
Cummings
Derek A T
DA
Bous
Sophia M
SM
Keaton
Amelia
A
Balog
Joan Z
JZ
Hadley
Donald
D
Zhou
Nan
N
Long
Robert
R
Vélez
Jorge I
JI
Pineda-Alvarez
Daniel E
DE
Odent
Sylvie
S
Roessler
Erich
E
Muenke
Maximilian
M
D005260:Female; D005838:Genotype; D016142:Holoprosencephaly / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D014157:Transcription Factors / Q000235:genetics*
D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human