Hydrocephalus Panel

Hydrocephalus is a complex condition influenced by both genetic and environmental factors. Congenital hydrocephalus affects 4.65 per 10,000 births (Shaheen et al. 2017. PubMed ID: 28556411). The genetic form of hydrocephalus can be caused by a group of heterogeneous disorders affecting the ventricular system of the brain with excessive accumulation of cerebrospinal fluid (CSF). It can present either in an isolated form (congenital or pure hydrocephalus) or in conjunction with other genetic anomalies. The symptoms of hydrocephalus vary with age, cause, and disease progression. Onset can be prenatal. In infancy, the major features of hydrocephalus are characterized by a rapid increase in head circumference or an unusually large head size, vomiting, sleepiness, irritability, downward deviation of the eyes and seizures. In older children, clinical features may include headache, vomiting, nausea, blurred vision, downward deviation of the eyes, and gait disturbance. Additional features include developmental delay, intellectual disability, spasticity, and many other minor features specific to particular genes.

Cranial imaging techniques such as ultrasonography, CT, MRI, or pressure-monitoring techniques are useful in the diagnosis of patients with hydrocephalus (Shaheen et al. 2017. PubMed ID: 28556411; Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Ekici et al. 2010. PubMed ID: 21031079). As hydrocephalus can be caused by defect in many genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image study only. Therefore, an accurate molecular diagnosis become critical for treatment, prognosis, prediction of recurrence risk, as well as future family planning.

The genetic etiology of the Hydrocephalus is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms. Hydrocephalus can be inherited in an autosomal dominant, autosomal recessive and X-linked manner or through complex inheritance. In this panel, we mainly focus on familial, congenital hydrocephalus causative genes, as well as genes for other genetic disorders with hydrocephalus (Shaheen et al. 2017. PubMed ID: 28556411; Jin et al. 2020. PubMed ID: 33077954). The type of pathogenic variant varies with different genes; for example, the majority of pathogenic variants in L1CAM and AP1S2 are truncating variants, whereas those in CCND2 are missense variants (Human Gene Mutation Database).

The selected genes are involved in cellular processes, such as neural cell adhesion (L1CAM), planar cell polarity (MPDZ), the Wingless/integrated WNT signaling pathway (CCDC88C), or vesicle transport within the cell (AP1S2) (Shaheen et al. 2017. PubMed ID: 28556411; Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Ekici et al. 2010. PubMed ID: 21031079; Cacciagli et al. 2014. PubMed ID: 23756445).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

This panel focuses on isolated hydrocephalus, as well as disorders with ventriculomegaly as one of their symptoms. The sensitivity is variable depending on different disorders. For example, the most common heritable form is caused by pathgenic variants in L1CAM and accounts for up to 10% of males with X-linked isolated idiopathic hydrocephalus. In this panel, the most common causative genes are L1CAM, AP1S2, MPDZ and CCDC88C (Al-Jezawi et al. 2018. PubMed ID: 29499638).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.3% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).