| Summary: | The aim of this study was to identify susceptibility genes for the common disease Infantile Hypertrophic Pyloric Stenosis (IHPS) using a whole genome screening approach. IHPS is a form of gastrointestinal obstruction with an incidence between 1 and 5 per 1000 live births. It is characterized by hypertrophy of the pyloric smooth muscle, which develops after birth in response to enteral feeds and leads to gastric outlet obstruction with projectile vomiting. IHPS is commonly inherited as a multifactorial trait with a marked male preponderance but monogenic and syndromic forms are also described. Molecular genetic studies have previously identified two IHPS predisposing regions (IHPS1 [MIM #179010] and IHPS2 [MIM #610260]), which seem to account for a small subset of IHPS cases. DNA samples from over 500 IHPS families were collected in total. This work included the molecular analysis of a proportion of those families. A pedigree with 8 affected individuals was analysed using a SNP-based genome-wide linkage scan and a locus for monogenic IHPS on chromosome 16q24 was identified (LOD score 3.7). Analysis of candidate gene SLC7A5 did not reveal any mutations and analysis of 14 further multiplex pedigrees for evidence of linkage to 16q24 did not result in significant LOD scores supporting locus heterogeneity. Additionally, a SNP-based genome-wide linkage analysis of 81 pedigrees identified 2 more IHPS predisposing loci on chromosomes 11q14-q22 (Z_max= 3.9, p<0.0001; HLOD_max = 3.4, alpha = 0.34) and Xq23 (Z_max = 4.3, p<0.00001; HLOD_max = 4.8, alpha = 0.56), and a region of potential interest on chromosome 3, (Z_max = 2.70, p<0.003; HLOD_max = 1.78, alpha=0.52). These three regions each harbor candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels raising the hypothesis that IHPS may be a channelopathy.
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