Hydrocephalus, Congenital 2 with or without Brain or Eye Anomalies via the MPDZ Gene

Hydrocephalus, congenital, 2 with or without brain or eye anomalies is non-syndromic hydrocephalus with prenatal onset. Other symptoms can include intellectual disability, seizures, developmental motor delay, congenital heart septal defects, and varying degrees of dysmorphic facial features. Multiple ependymal malformations have also been observed in patients. In addition, eye anomalies can include optic atrophy, acular hypoplasia and foveal dysplasia. Prenatal ultrasound may reveal macrocephaly with severe bilateral or isolated ventriculomegaly. Brain MRI may show massive hydrocephalus (Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Shaheen et al. 2017. PubMed ID: 28556411).

Hydrocephalus, congenital, 2 with or without brain or eye anomalies is inherited in an autosomal recessive manner and is caused by pathogenic variants in the MPDZ gene. MPDZ encodes the multiple PDZ domain protein. Pathogenic variants in MPDZ gene include missense, nonsense, splicing and small frameshift deletions. Large deletions and duplications have not been reported yet at the MPDZ locus (Human Gene Mutation Database). A founder effect due to certain pathogenic variants has been reported in Saudi patients (Shaheen et al. 2017. PubMed ID: 28556411).

MPDZ localizes at cellular junctions and its multiple domains bind multivalent scaffold proteins which regulate intracellular signaling, receptor clustering and polarity of epithelial cells (Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Shaheen et al. 2017. PubMed ID: 28556411).

Clinical sensitivity of MPDZ in a large cohort of patients with congenital hydrocephalus and other relevant phenotypes is unavailable in the literature, because most of the studies are case reports. MPDZ is one of the important genes for congenital hydrocephalus.

This test provides full coverage of all coding exons of the MPDZ gene 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 full 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).