Abstract
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.
Highlights
(HPE) is a very common developmental disorder defined as a failure in midline patterning of the forebrain and/or midface (Muenke and Beachy, 2001; Tekendo-Ngongang et al, 2020)
HPE is almost certainly caused by a complex set of genetic and environmental risk factors (Figure 2)
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 patterning
Summary
(HPE) is a very common developmental disorder defined as a failure in midline patterning of the forebrain and/or midface (Muenke and Beachy, 2001; Tekendo-Ngongang et al, 2020). An unbroken continuum of HPE phenotypes (sometimes called the HPE spectrum) is broadly classified into three categories based on the degree of midline cleavage of the forebrain (Muenke and Beachy, 2001; Tekendo-Ngongang et al, 2020). Alobar HPE, the most severe form, is characterized by complete failure to partition the forebrain into left and right hemispheres, resulting in a single, centrally-located ventricle. Semilobar and lobar HPE are progressively less severe forms and display partial, or mostly complete, forebrain cleavage, respectively. Mild facial midline abnormalities may occur without clinically obvious brain malformations and are called HPE microforms
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