title: Molecular prenatal diagnosis of a sporadic alobar holoprosencephalic fetus: genotype-phenotype correlations.
abstract: OBJECTIVE
  holoprosencephaly is the most common forebrain malformation syndrome with a multifactorial etiology. Currently, mutations are identified in 5-10% of non syndromic, non-chromosomal cases in at least 12 genes. We report the molecular prenatal diagnosis of a fetus with alobar holoprosencephaly.
  
  
  METHODS
  CTG band karyotyping and array CGH genome-wide cytogenetic screenings were done, in conjunction with DNA sequence analyses of the SHH, ZIC2, SIX3 and TGIF genes in search of a molecular etiology and with comparison of findings to prior cases.
  
  
  RESULTS
  standard CTG band karyotyping and array CGH genome-wide screening failed to identify plausible chromosome imbalances or structural anomalies. However, extensive sequencing of the genomic DNA from the fetus and both parents on all exon and exon-intron boundaries of the four most commonly mutated genes: SHH, ZIC2, SIX3 and TGIF, identified codon 100 of the sonic hedgehog (SHH) gene having a hotspot for loss-of-function mutations in our case and others.
  
  
  CONCLUSIONS
  mutations in codon 100 of SHH were discovered in both sporadic and autosomal dominant inherited cases with evidence of variable expressivity and penetrance. Collectively, this study reinforces the complexity of genotype-phenotype correlations in the prenatal diagnosis of holoprosencephalic fetuses.
authors.affiliation: Human Genetics Research Unit, Centre de recherche de l'Hôpital Saint-François d'Assise, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gekas
authors.forename: Consolato
authors.initials: C
authors.lastname: Sergi
authors.forename: Deepak
authors.initials: D
authors.lastname: Kamnasaran