Unveiling the Molecular Landscape of Dandy-Walker Syndrome

Dandy-Walker syndrome or Dandy-Walker Malformation (DWM) causes an upward rotation of the cerebellar vermis and hypoplasia, as well as cystic inflation of the fourth ventricle which affects one in every 5000 live births (MIM:220200). Motor impairments such as hypotonia, ataxia and delayed motor development are common in affected persons and roughly some have hydrocephalus and half have mental retardation. The main causes of this malformation are chromosomal anomalies, duplications, microdeletions and some de novo mutations in six genes. The two genetic loci 3q24 and 6p25.3 on human chromosomes have been identified that cause DWM. The related genes ZIC1 and ZIC4 are associated for developing cerebellum granule neurons precursor. The decrease expression of these GNPs could explain cerebellar hypoplasia due to deletion 3q24. It is important to distinguish DWM from malformations that have less severe cerebellar vermis hypoplasia, less noticeable or nonexistent upward vermis rotation, and frequently less posterior fossa fluid accumulation. Children with DWM have seizure and apnea and are hypotonic on physical examination which develop spasticity later. In this study, family from a PIMS hospital Islamabad Pakistan was examined. After a physical examination and magnetic resonance imaging, the proband was determined to have DWM. Sanger sequencing was used to examine the molecular underlying cause and pathogenic variant linked to the family's DWM. By examining the probands' sequencing results, we did not find any pathogenic missense, frameshift, or disease-causing mutations in the targeted gene ZIC1 that resulted in the hydrocephalous DWM. Further study should be suggested by performing Whole Exome Sequencing (WES) to characterize the molecular pathogenic variants that causes the malformation.