Gene-environment interactions in rare diseases that include common birth defects

Abstract

Rare syndromes often feature specific types of birth defects that frequently are major diagnostic clues to the presence of a given disorder. Despite this specificity, not everyone with the same syndrome is equally or comparably affected, and not everyone with a specific birth defect manifests the same syndrome or is affected with all the features of a particular syndrome. A symposium sponsored by the National Institutes of Health Office of Rare Diseases, and the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction attempted to explore how much of this variability is due to genetic factors and how much is due to environmental factors. The specific types of birth defects examined included cardiovascular defects, holoprosencephaly, clefts of the lip and/or palate, neural tube defects, and diaphragmatic hernias.

Evidence of gene‐environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate

“…The interaction between susceptibility genes and common environment factors can also influence the etiology of nonsyndromic oral clefts (Graham and Shaw, 2005; Young et al, 2007). Considering GxE interaction will identify more risk loci, lead to better understanding of underlying biologic mechanisms, and provide information for designing effective preventive strategies.…”

Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left–right patterning defects

“…The role of gene–environment interaction in determining phenotypes in the developing mammalian embryo is only beginning to be understood, and has major a significance in understanding and preventing birth defects (18). The results presented here identify a hitherto unknown gene–environment interaction between a genetic deficiency in Cited2 and a maternal high-fat diet that affects Pitx2c expression, and strikingly enhances penetrance of embryonic left–right patterning and palatal defects.…”

“…Although the role of both genetic causes and factors that affect the intrauterine environment (such as maternal rubella and teratogen exposure) in human congenital heart disease is well established (reviewed in 17), the mechanisms by which environmental factors interact with genetic variants to cause birth defects is only beginning to be understood (reviewed in 18). A new and important source of environmental risk to the developing fetus is the growing epidemic of obesity in women of reproductive age (19,20).…”

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening

“…Isolated CLP represents the most common birth defect form of newborns occurring in approximately 1/700 births. The etiological basis for both HPE and CLP is poorly understood, with the preponderance of evidence suggesting an interaction of genetic predisposition with environmental and/or chemical influences (Murray, 2002; Graham and Shaw, 2005; Dubourg et al, 2007, Gritle-Linde, 2009; Schachter and Krauss, 2009). The Hh pathway is a tantalizing common target for such interactions.…”