Infantile hypertrophic pyloric stenosis: evaluation of three positional candidate genes, TRPC1, TRPC5 and TRPC6, by association analysis and re-sequencing

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy with a striking male preponderance. Infants present with vomiting due to gastric outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. Two loci specific to extended pedigrees displaying autosomal dominant inheritance have been identified. A genome scan identified loci on chromosomes 11q14-q22 and Xq23-q24 which are predicted to be responsible for a subset of smaller families with IHPS demonstrating non-Mendelian inheritance. The two linked chromosomal regions both harbour functional candidate genes which are members of the canonical transient receptor potential (TRPC) family of ion channels. Both TRPC5 (Xq23-q24) and TRPC6 (11q14-q22) have a potential role in smooth muscle control and hypertrophy. Here, we report suggestive evidence for a third locus on chromosome 3q12-q25 (Z (max) = 2.7, p < 0.004), a region which harbours a third TRPC gene, TRPC1. Fine mapping of all three genes using a tagSNP approach and re-sequencing identified a SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 which may be putative causal variants.