title: Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.
abstract: 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.
authors: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Benjamin D
authors: BD
authors: Solomon
authors: Felicitas
authors: F
authors: Lacbawan
authors: Sandra
authors: S
authors: Mercier
authors: Nancy J
authors: NJ
authors: Clegg
authors: Mauricio R
authors: MR
authors: Delgado
authors: Kenneth
authors: K
authors: Rosenbaum
authors: Christèle
authors: C
authors: Dubourg
authors: Veronique
authors: V
authors: David
authors: Ann Haskins
authors: AH
authors: Olney
authors: Lars-Erik
authors: LE
authors: Wehner
authors: Ute
authors: U
authors: Hehr
authors: Sherri
authors: S
authors: Bale
authors: Aimee
authors: A
authors: Paulussen
authors: Hubert J
authors: HJ
authors: Smeets
authors: Emily
authors: E
authors: Hardisty
authors: Anna
authors: A
authors: Tylki-Szymanska
authors: Ewa
authors: E
authors: Pronicka
authors: Michelle
authors: M
authors: Clemens
authors: Elizabeth
authors: E
authors: McPherson
authors: Raoul C M
authors: RC
authors: Hennekam
authors: Jin
authors: J
authors: Hahn
authors: Elaine
authors: E
authors: Stashinko
authors: Eric
authors: E
authors: Levey
authors: Dagmar
authors: D
authors: Wieczorek
authors: Elizabeth
authors: E
authors: Roeder
authors: Chayim Can
authors: CC
authors: Schell-Apacik
authors: Carol W
authors: CW
authors: Booth
authors: Ronald L
authors: RL
authors: Thomas
authors: Sue
authors: S
authors: Kenwrick
authors: Derek A T
authors: DA
authors: Cummings
authors: Sophia M
authors: SM
authors: Bous
authors: Amelia
authors: A
authors: Keaton
authors: Joan Z
authors: JZ
authors: Balog
authors: Donald
authors: D
authors: Hadley
authors: Nan
authors: N
authors: Zhou
authors: Robert
authors: R
authors: Long
authors: Jorge I
authors: JI
authors: Vélez
authors: Daniel E
authors: DE
authors: Pineda-Alvarez
authors: Sylvie
authors: S
authors: Odent
authors: Erich
authors: E
authors: Roessler
authors: Maximilian
authors: M
authors: Muenke
mesh_terms: 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*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human