Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly

Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.

Automated summary

Many common developmental disorders are believed to be caused by a combination of genetic and environmental risk factors, which interact to affect key developmental signaling pathways and potentially lead to abnormal embryonic patterning. Holoprosencephaly (HPE) serves as a model system for understanding multifactorial etiology, with studies showing various ways in which risk factors interact to produce adverse developmental outcomes. This includes interactions between genes, oligogenic inheritance, interactions between genetic susceptibilities and environmental factors, and interactions between genetic and non-genetic risk factors. These concepts are applicable not only to HPE but also to other disorders with complex origins.