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. Wh...
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2021-06-01
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Series: | Acta Neuropathologica Communications |
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Online Access: | https://doi.org/10.1186/s40478-021-01207-5 |
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doaj-a05c3f30da5b41a0a0d5ebe0f0978624 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Florent Marguet Myriam Vezain Pascale Marcorelles Séverine Audebert-Bellanger Kévin Cassinari Nathalie Drouot Pascal Chambon Bruno J. Gonzalez Arie Horowitz Annie Laquerriere Pascale Saugier-Veber |
spellingShingle |
Florent Marguet Myriam Vezain Pascale Marcorelles Séverine Audebert-Bellanger Kévin Cassinari Nathalie Drouot Pascal Chambon Bruno J. Gonzalez Arie Horowitz Annie Laquerriere Pascale Saugier-Veber Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants Acta Neuropathologica Communications CCDC88C pathogenic variants Autosomal recessive inheritance Foetal hydrocephalus Neuropathology Multiple ependymal malformations Choroid plexus hydrops |
author_facet |
Florent Marguet Myriam Vezain Pascale Marcorelles Séverine Audebert-Bellanger Kévin Cassinari Nathalie Drouot Pascal Chambon Bruno J. Gonzalez Arie Horowitz Annie Laquerriere Pascale Saugier-Veber |
author_sort |
Florent Marguet |
title |
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants |
title_short |
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants |
title_full |
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants |
title_fullStr |
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants |
title_full_unstemmed |
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants |
title_sort |
neuropathological hallmarks of fetal hydrocephalus linked to ccdc88c pathogenic variants |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2021-06-01 |
description |
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. |
topic |
CCDC88C pathogenic variants Autosomal recessive inheritance Foetal hydrocephalus Neuropathology Multiple ependymal malformations Choroid plexus hydrops |
url |
https://doi.org/10.1186/s40478-021-01207-5 |
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doaj-a05c3f30da5b41a0a0d5ebe0f09786242021-06-13T11:35:41ZengBMCActa Neuropathologica Communications2051-59602021-06-01911710.1186/s40478-021-01207-5Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variantsFlorent Marguet0Myriam Vezain1Pascale Marcorelles2Séverine Audebert-Bellanger3Kévin Cassinari4Nathalie Drouot5Pascal Chambon6Bruno J. Gonzalez7Arie Horowitz8Annie Laquerriere9Pascale Saugier-Veber10UNIROUEN, INSERM U1245, Rouen University Hospital, Department of Pathology, Normandie UnivUNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie UnivUBO EA 4685 LIEN and Brest University Hospital, Pathology Department, Brest UnivDepartment of Genetics, Brest University HospitalUNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie UnivUNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie UnivUNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie UnivUNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie UnivUNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie UnivUNIROUEN, INSERM U1245, Rouen University Hospital, Department of Pathology, Normandie UnivUNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie UnivAbstract 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.https://doi.org/10.1186/s40478-021-01207-5CCDC88C pathogenic variantsAutosomal recessive inheritanceFoetal hydrocephalusNeuropathologyMultiple ependymal malformationsChoroid plexus hydrops |