A novel missense mutation in the transcription factor FOXF1 cosegregating with infantile hypertrophic pyloric stenosis in the extended pedigree linked to IHPS5 on chromosome 16q24.

BACKGROUND: The aim was to identify susceptibility alleles for infantile hypertrophic pyloric stenosis (IHPS) in a pedigree previously linked to IHPS5 on chromosome 16q24.
METHODS: We screened the positional and functional candidate gene FOXF1 by Sanger sequencing in a single affected individual. All family members for whom DNA was available were genotyped to determine cosegregation status of the putative causal variant. Immunofluorescence studies were performed to compare the cellular localization of wildtype and mutant form of the protein. Transcriptional activity was compared using a luciferase assay.
RESULTS: A single novel substitution in FOXF1 (c.416G>A) predicted to result in a missense mutation (R139Q) was shown to cosegregate with disease trait. It was not seen in 560 control chromosomes nor has it been reported in ExAC or ESP. The R139Q substitution affects a conserved arginine residue within the DNA-binding domain of FOXF1. The transcriptional activity of the mutant FOXF1 protein is significantly reduced in comparison to wild-type.
CONCLUSION: These results provide strong evidence that the R139Q substitution in FOXF1 causes IHPS in this family and imply a novel pathological pathway for the condition. They further support a role for FOXF1 in the regulation of embryonic and neonatal development of the gastro-intestinal tract.