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Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants.

ABSTRACT: The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.

SUBMITTER: Marguet F

PROVIDER: S-EPMC8183048 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceAlthough increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications.ObjectiveTo test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size.Design, setting, and participantsThis autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016.Main outcomes and measurementsResults of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor α (LXRα), and adenosine triphosphate-binding cassette transporter 1 (ABCA1).ResultsAmong the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P = .001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, -0.534 and -0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed.Conclusions and relevanceThe present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies.

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Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants.

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