title: Unique alterations of an ultraconserved non-coding element in the 3'UTR of ZIC2 in holoprosencephaly.
abstract: Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Sung-Kook
authors.initials: SK
authors.lastname: Hong
authors.forename: Kshitij
authors.initials: K
authors.lastname: Srivastava
authors.forename: Blake
authors.initials: B
authors.lastname: Carrington
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.forename: Hanna
authors.initials: H
authors.lastname: Petrykowska
authors.forename: Laura
authors.initials: L
authors.lastname: Elnitski
authors.forename: Lucilene A
authors.initials: LA
authors.lastname: Ribeiro
authors.forename: Antonio
authors.initials: A
authors.lastname: Richieri-Costa
authors.forename: Benjamin
authors.initials: B
authors.lastname: Feldman
authors.forename: Ward F
authors.initials: WF
authors.lastname: Odenwald
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D016548:Prosencephalon / Q000254:growth & development; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish
chemical_list: D020413:3' Untranslated Regions; D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human