Figure 4. Algorithm for molecular analysis in HPE
In cases of familial HPE, analyses of SHH, SIX3 or TGIF should be given priority over ZIC2 analysis. Very severe forms of HPE, such as alobar and semilobar HPE, should lead to analyses of the SIX3 (particularly in cases of atelencephaly/aprosencephaly) and ZIC2 genes, but facial features may provide useful information. Indeed, probands with category 1 or 2 facial features associated with severe HPE, such as alobar or semilobar HPE, are more likely to display mutations in SIX3 or SHH. By contrast, probands with severe brain malformations and category 4 facial features are likely to have mutations in ZIC2. No particular association with lobar HPE was found. Thus, if associated brain malformations are described, particularly in cases of neuronal migration abnormalities, and in cases of neuronal tube defects (rachischisis in particular), ZIC2 gene analysis should be performed as a matter of priority. Moreover, ZIC2 mutations are the principal cause of extracraniofacial malformations. Renal/urinary malformations are found preferentially in patients with ZIC2 or SHH mutations and coloboma tends to be found in patients with SHH or SIX3 mutations.