Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations

Hum Mutat. 2004 Jul;24(1):43-51. doi: 10.1002/humu.20056.


Holoprosencephaly (HPE; 1 out of 16,000 live births; 1 out of 250 conceptuses) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, affecting both the forebrain and the face. Clinical expressivity is variable, ranging from a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial dominant autosomic HPE. The disease is genetically heterogeneous, but additional environmental agents also contribute to the etiology of HPE. In our cohort of 200 patients, 34 heterozygous mutations were identified, 24 of them being novel ones: 13 out of 17 in the Sonic hedgehog gene (SHH); 4 out of 7 in ZIC2; and 7 out of 8 in SIX3. The two mutations identified in TGIF have already been reported. Novel phenotypes associated with a mutation have been described, such as abnormalities of the pituitary gland and corpus callosum, colobomatous microphthalmia, choanal aperture stenosis, and isolated cleft lip. This study confirms the great genetic heterogeneity of the disease, the important phenotypic variability in HPE families, and the difficulty to establish genotype-phenotype correlations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Chromosome Deletion
  • Codon, Nonsense / genetics
  • Cohort Studies
  • DNA Mutational Analysis / methods*
  • Exons / genetics
  • Eye Proteins
  • Female
  • Fetal Diseases / genetics
  • Genetic Heterogeneity
  • Genotype
  • Hedgehog Proteins
  • Holoprosencephaly / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins
  • Phenotype
  • Pregnancy
  • Pregnancy Outcome
  • Repressor Proteins / genetics*
  • Trans-Activators / genetics*
  • Transcription Factors / genetics*


  • Codon, Nonsense
  • Eye Proteins
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • SHH protein, human
  • Sine oculis homeobox homolog 3 protein
  • TGIF1 protein, human
  • Trans-Activators
  • Transcription Factors
  • ZIC2 protein, human