Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms

Abstract

The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

Keywords: Central system; Cilia; Congenital hydrocephalus; Genetic disease; Ventricle.

Fig. 1

The production of CSF occurs through two distinct pathways: the choroid plexus and the brain parenchymal system. CSF can be absorbed by the subarachnoid space or glymphatic circulation, ultimately entering the dcLNs. CSF cerebrospinal fluid, dcLNs deep cervical lymphatic nodes, ISF interstitial fluid, mLVs meningeal lymphatic vessels

Fig. 2

The genetic targets of CH in humans involve genes related to cilia movement, Sylvius aqueduct development, and nervous system growth in pathological cases of CH. CH congenital hydrocephalus, FOXJ1 forkhead box J1, CWH43 cell wall biogenesis 43 C-terminal homolog, AK9 adenylate kinase 9, AP1S2 adaptor related protein complex 1 subunit sigma 2, CCDC88C coiled-coil domain containing 88C, L1CAM L1 cell adhesion molecule, TR1M71 tripartite motif containing 71, SMARCC1 SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 1, PTCH1 patched 1, SHH sonic hedgehog, MPDZ multiple PDZ domain crumbs cell polarity complex component, CRB2 crumbs cell polarity complex component 2

Fig. 3

Genes associated with CH identified in animal models. In zebrafish and mouse models, genes linked to the development of hydrocephalus can be categorized into 4 distinct groups: cilia synthesis and movement-related, ion transporter-related, RF synthesis-related, cell apoptosis and neurogenesis-related, etc. RF Reissner’s fiber, CH congenital hydrocephalus, CNS central nervous system, CaV1.2 calcium voltage-gated channel subunit alpha1 C, Calb2 calbindin 2, Atp1a3 ATPase Na⁺/K⁺ transporting subunit α3, Slc41a1 solute carrier family 41 members 1, Pank2 pantothenate kinase 2, Ccdc85c coiled-coil domain containing 85C, Lgi1b leucine-rich glioma inactivated 1b, Ecrg4 esophageal cancer related gene 4, Wdr16 cilia and flagella associated protein 52, Nphp7 nephrocystin 7, Ccp5 cytosolic carboxypeptidases 5, Exoc5 cxocyst complex component 5, Msx1 Msh homeobox 1, Hrg1 solute carrier family 48 member 1, b-Pix Rho guanine nucleotide exchange factor (GEF) 7b