The embryological process that leads to hemisphere separation is estimated to completely or partially fail in approximately 1/172 human conceptuses, resulting in the most common structural defect of the human forebrain, Holoprosencephaly (HPE). The frequency of HPE cases drops drastically to 1/10 000 at birth, indicating a high level (98%) of embryonic lethality and highlighting the crucial nature of hemisphere separation during development. ZIC2is one of four genes that are considered major contributors to the congenital birth defect HPE.
Forebrain malformation
HPE is characterised by the region in which forebrain separation fails, either ventrally or dorsally, resulting in classic or middle interhemispheric variant (MIHV) HPE, respectively. Majority of patients with mutations in ZIC2present with classic HPE. Clinical presentations of classic HPE exist on a spectrum and are further anatomically classified according to the degree of forebrain separation. This spectrum ranges from the least severe, lobar HPE (hemispheric and lateral vesicle separation is retained, except for in the rostral and ventral frontal lobes), followed by semilobar (partial hemispheric separation, resulting in fused left and right frontal and parietal lobes but retaining the posterior portion of the interhemispheric fissure) and the the most severe form, alobar HPE (a monohemisphere with no hemispheric separation). In comparison to HPE as a whole, ZIC2-associated HPE manifests as highly penetrant (93%) with relatively few mild phenotype individuals. It is estimated that 90% of patients with a ZIC2mutation exhibit structural brain anomalies and accompanying neurological impairment.
Craniofacial defects
A subtle but distinct craniofacial phenotype can be seen in ZIC2-associated HPE cases, consisting of (but not always containing) bitemporal narrowing, upslanted palpebral fissures, a flat nasal bridge, short nose with anteverted nares, a broad and deep philtrum and the appearance of large ears. Whilst facial clefts occurred in both non-ZIC2and ZIC2-associated HPE, the frequency is reduced by 1/3 in the latter.
Other non-forebrain phenotypes
HPE patients with intragenic ZIC2mutations have been found to exhibit neural tube defects (4%), hydrocephalus (12%), skeletal anomalies (14%), cardiac anomalies (9%) and renal anomalies (7%).
ZIC2