We recently reported that transgenic mice with one interrupted allele of a brain-specific transcript variant of the winged helix transcription factor, RFX4_v3, exhibited universal congenital hydrocephalus with aqueductal stenosis and agenesis of the subcommissural organ. Mice with two interrupted alleles had severe brain midline malformations and died in utero. To investigate the hypothesis that haploinsufficiency at the RFX4 locus might lead to human congenital hydrocephalus with aqueductal stenosis, we will: a) evaluate patients diagnosed with congenital hydrocephalus for deletion of the RFX4 locus and b) evaluate patients diagnosed with an interstitial deletion in the long arm of chromosome 14 that is predicted to include the RFX4 locus for hydrocephalus.
This is an observational cohort study that includes patients either diagnosed with congential hydrocephalus or patients diagnosed with interstitial deletion in the long arm of chromosome 14. We will use real-time PCR analysis, using several primer sets, to examine the RFX4 DNA copy number in genomic DNA which has previously been isolated from the patients (and their parents, if available). In cases where the patient has not been clinically diagnosed with hydrocephalus, we will analyze previously imaged MRI scans to look for evidence of either hydrocephalus or aqueductal stenosis in the patient. This proposed study will allow us to determine whether the haploinsufficiency phenotype seen in the mouse might translate directly to man.