HPE shows marked incomplete penetrance (with only ~70% of individuals who carry HPE pathogenic mutations exhibiting HPE symptoms) and variable expressivity ( identical mutations can result in widely differing phenotypes between affected individuals.), Furthermore, the high in-utero frequency of HPE further suggests a multi-factorial causation. These features suggest that additional modifying factors influence disease outcome.
Evidence from both human studies and animal models demonstrates that genetic background and environmental exposures contribute to phenotypic variability in HPE. Accordingly, a central consideration in HPE research is the combined signalling activity achieved across key embryonic pathways that regulate anterior midline formation.
Current research efforts focus on investigating not only the direct effects of ZIC2loss-of-function variants, but also how these variants interact with other genetic factors and the maternal environment during early embryogenesis. This includes studies examining gene–gene interactions as well as gene–environment interactions that may modify disease risk and severity.
A leading hypothesis is that pathogenic ZIC2variants sensitise the developing embryo to environmental teratogens, such that exposure to one or more adverse factors during critical windows of development precipitates the HPE phenotype. Candidate environmental modifiers include known teratogens, such as alcohol, which may further disrupt signalling pathways essential for forebrain patterning. These interaction-based mechanisms may help explain why heterozygous mutations in ZIC2, and other HPE-associated genes, are sufficient to cause disease in some but not all carriers.
ZIC2