A new mutation in the six-domain of SIX3 gene causes holoprosencephaly.

Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region.