Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature

Abstract

Holoprosencephaly (HPE) is a major structural birth defect of the brain that occurs in approximately 1 in 10,000 live births. Although some genetic causes of HPE are known, a substantial proportion of cases have an unknown etiology. Due to the low birth prevalence and rarity of exposure to many potential risk factors for HPE, few epidemiologic studies have had sufficient sample size to examine risk factors. A 2010 review of the literature identified several risk factors that had been consistently identified as occurring more frequently among cases of HPE, including maternal diabetes, twinning, and a predominance of females, while also identifying a number of potential risk factors that had been less widely studied. In this article, we summarize a systematic literature review conducted to update the evidence for nongenetic risk factors for HPE.

A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats

“…In humans, HPE is the most common malformation of the prosencephalon, and its prevalence is approximate 1 in 10,000 births [ 47 ]. A common feature of HPE includes the incomplete separation of the anterior part of the forebrain or telencephalon.…”

“…In humans, heterogeneity in familial HPE is also identified even if different individuals are carrying the same mutation [ 52 , 53 , 54 ]. The influence of environmental or teratogenic factors or modifier genes have been suggested for the spectrum (reviewed in [ 47 , 48 , 50 ]). Assuming no exposure to teratogen and relatively homogeneous living environment, the presence of modifier genes is suspected for the variable severity of the dilated ventricles and supratentorial cysts in cats presented here.…”

A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

“…In humans, HPE is the most common malformation of the prosencephalon, and its prevalence is approximate 1 in 10,000 births [46]. A common feature of HPE includes the incomplete separation of the anterior part of the forebrain or telencephalon.…”

“…In humans, heterogeneity in familial HPE is also identified even if different individuals are carrying the same mutation [51][52][53]. The influence of environmental or teratogenic factors or modifier genes have been suggested for the spectrum (Reviewed in [46,47,49]). Assuming no exposure to teratogen and relatively homogeneous living environment, the presence of modifier genes is suspected for the variable severity of the dilated ventricles and supratentorial cysts in cats presented here.…”

Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly

“…The etiology of HPE is complex, involving both genetic and environmental risk factors ( Addissie et al, 2020 ; Dubourg et al, 2018 ; Hong and Krauss, 2018 ; Johnson and Rasmussen, 2010 ; Krauss, 2007 ; National Birth Defects Prevention Study et al, 2010 ; Muenke and Beachy, 2001 ; NISC Comparative Sequencing Program et al, 2018 ; Roessler et al, 2018 ; Summers et al, 2018 ). Heterozygous, loss-of-function mutations in components or regulators of the HH, Nodal, and FGF signaling pathways are associated with HPE ( NISC Comparative Sequencing Program et al, 2018 ; Roessler et al, 2018 ).…”