Genetic Variation of RFX4 in Congenital Hydrocephalus
Gene Environmental Interactions Group
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.
Study Design
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.