Holoprosencephaly (HPE) is a severe congenital malformation of the forebrain and face that results from a failure of anterior midline formation. The forebrain presents with a structural defect caused by a failure of the cerebral hemispheres to separate during early embryogenesis. This leads to a spectrum of structural brain abnormalities with variable clinical severity. Since the ventral forebrain and facial midline have a shared dependency upon certain embryological and molecular events, the structural brain defects are generally accompanied by craniofacial dysmorphologies. ZIC2-associated HPE is distinguished by a comparative lack of craniofacial anomalies.
Main clinical features
Based on the pattern and extent of hemispheric non-separation, HPE is broadly classified into two main forms: classic holoprosencephaly and the middle interhemispheric variant (MIHV). Within classic HPE, severity ranges from alobar (most severe), to semilobar, to lobar (least severe).
Pathogenic variants in ZIC2predominantly cause brain malformations rather than craniofacial anomalies, however, individuals with ZIC2- associated HPE often have a subtle but distinct craniofacial phenotype. Characteristic neuroanatomical findings include incomplete separation of the thalami, agenesis of the corpus callosum, and absent or hypoplastic olfactory and optic bulbs and tracts. Affected individuals frequently present with neurodevelopmental delay and seizure disorders.
Prevalence
Holoprosencephaly is the most frequent congenital brain malformation, occurring in 1 in 10,000 live births and 1 in 172 conceptuses.
Inheritance
HPE is a heterogeneous disorder with multiple underlying causes and several modes of heredity. The majority of mutations that cause HPE are de novo in nature. The condition is typically considered autosomal dominant; however, it does not exhibit Mendelian inheritance, with only ~70% of individuals who carry HPE mutations exhibiting HPE symptoms.
ZIC2