title: Comparison of mutation findings in ZIC2 between microform and classical holoprosencephaly in a Brazilian cohort.
abstract: BACKGROUND
  Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes.
  
  
  METHODS
  We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups.
  
  
  RESULTS
  We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues).
  
  
  CONCLUSIONS
  From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.
authors: Molecular Genetics Laboratory and Clinical Genetics Service, Hospital for Rehabilitation and Craniofacial Anomalies, University of Sao Paolo, Bauru, Sao Paolo, Brazil.
authors: Lucilene A
authors: LA
authors: Ribeiro
authors: Erich
authors: E
authors: Roessler
authors: Ping
authors: P
authors: Hu
authors: Daniel E
authors: DE
authors: Pineda-Alvarez
authors: Nan
authors: N
authors: Zhou
authors: Marypat
authors: M
authors: Jones
authors: Settara
authors: S
authors: Chandrasekharappa
authors: Antonio
authors: A
authors: Richieri-Costa
authors: Maximilian
authors: M
authors: Muenke
mesh_terms: D000328:Adult; D000483:Alleles; D001938:Brazil / Q000453:epidemiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006639:Histidine / Q000235:genetics; D016142:Holoprosencephaly / Q000145:classification / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D058889:Molecular Typing; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D044469:Racial Groups; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human; D006639:Histidine