[Genetic study of holoprosencephaly]

Holoprosencephaly (1/16,000 live births; 1/250 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 ventricule and cyclopia to clinically unaffected carriers in familial dominant autosomic holoprosencephaly. The disease is genetically heterogeneous but additional environmental agents also contribute to the aetiology of holoprosencephaly. In our cohort of 143 patients, 28 heterozygous mutations were identified: 15 in the Sonic hedgehog gene (SHH), 6 in ZIC2, 5 in SIX3, and 2 in TGIF. Functional tests have been set up to validate the significance of SHH amino acids replacements. 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 holoprosencephalic families, and the absence of evident genotype-phenotype correlations.