The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

Purpose Optic nerve head (ONH) atrophy is frequently associated with hydrocephalic conditions. Cerebrospinal fluid (CSF)-containing meninges form a subarachnoid space that terminates at the ONH, which physically impacts it. This study aims to characterize optic neuropathy in congenital hydrocephalic mice with genetic disruption of the Ccdc13 gene. Methods The ccdc13 germline knockout mice were generated. The hydrocephalus phenotype and subarachnoid space surrounding the optic nerve were evaluated using routine histology and Evans blue stain. Optic neuropathy was examined with immunohistochemistry and transmission electron microscopy (TEM). Axon transport was indicated by cholera toxin subunit B (CTB) fluorescence conjugate. Retinal function was evaluated by electroretinography (ERG), and Ccdc13 expression was revealed by a knock-in Gfp reporter. Results Ccdc13 mutant mice manifested hydrocephalus at birth. ONH displacement, or negative cupping, and enlarged subarachnoid space at the optic terminus occurred as early as 1 month after birth. Intraocular pressure (IOP) was normal. Optic neuropathy was first observed at the ONH, followed by a distal-to-proximal progression of optic nerve pathology indicated by alteration of axonal ultrastructure and deposition of unphosphorylated neurofilament heavy chain. Anterograde axonal transport was also hampered. Retinal ganglion cell (RGC) function was compromised as early as postnatal day 21 (P21), along with reduced neurofilament heavy chain expression. Optic neuropathy caused by disruption of Ccd13 was non-cell autonomous, stemming from hydrocephalus with presumed high intracranial pressure (ICP), which physically impacts the ONH by increasing the translaminar pressure gradient. Conclusions We provided knowledge of optic neuropathy from a congenital mouse model for hydrocephalus. The hydrocephalus in mice could damage the ONH by increasing the translaminar pressure gradient and negative cupping, leading to impairment in axoplasmic transport and RGC pathology. Our findings highlight the importance of the interplay between IOP and ICP in the development of glaucoma.

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Genetic etiology analysis of 73 fetuses with ventriculomegaly

Chenyue,

Huiqin,

Jingbo

et al. 2024

Preprint

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Objective High-throughput sequencing was performed on 73 fetuses with ventriculomegaly (VM) to analyze the genetic causes, including chromosomal aberrations and genetic variations.Methods The clinical data from fetuses with lateral ventricular width greater than 10 mm in second and third trimester were collected from Shanxi Provincial Children's Hospital between 2020 and 2023. Patient samples included amniotic fluid or miscarriage tissue and were evaluated via copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further examined using whole exome sequencing (WES), with chromosomal aberrations and genetic variations counted. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were followed.Results Of the 73 patients included in the study, 23 (31.5%) cases had chromosomal aberrations with 26 CNV fragments following CNV-seq, including 4 aneuploidies, 12 pathogenic variants, 2 likely pathogenic variants, and 8 variants of unknown significance. The detection rate of chromosomal aberrations was significantly higher in non-isolated VM relative to isolated VM. Negative CNV-seq results (n = 33) were further examined via WES, and a subset (n = 16, 48.48%) contained single-gene defects. These variants included SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1, and PURA, with 9 unreported variant loci also identified.Conclusion VM fetuses have complex developmental outcomes, and thus it is necessary to consider genetic etiology is VM. WES has the potential to provide a genetic diagnosis for VM fetuses without aneuploidy or CNVs, and can thereby increase the fetal VM diagnostic rate.

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The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

Cited by 4 publications

References 407 publications

Hydrocephalus: An update on latest progress in pathophysiological and therapeutic research

Hydrocephalus: An update on latest progress in pathophysiological and therapeutic research

Progressive Optic Neuropathy in Hydrocephalic Ccdc13 Mutant Mice Caused by Impaired Axoplasmic Transport at the Optic Nerve Head

Genetic etiology analysis of 73 fetuses with ventriculomegaly

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