Genome-wide High-Density SNP-Based Linkage Analysis of Infantile Hypertrophic Pyloric Stenosis Identifies Loci on Chromosomes 11q14-q22 and Xq23

Abstract

Infantile hypertrophic pyloric stenosis (IHPS) has an incidence of 1-8 per 1000 live births and is inherited as a complex sex-modified multifactorial trait with a striking male preponderance. Syndromic and monogenic forms exist, and two loci have been identified. Infants present with vomiting due to gastric-outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. A genome-wide SNP-based high-density linkage scan was carried out on 81 IHPS pedigrees. Nonparametric and parametric linkage analysis identified 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). The two linked chromosomal regions each harbor functional candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels and have a potential role in smooth-muscle control and hypertrophy.

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

“…sporadic patients and their parents, if available), all of Caucasian origin, were ascertained from the UK and Ireland. These families have been described in detail previously (Everett et al 2008b). The structures of the 12 pedigrees not consistent with linkage to either chromosome 11q14-q22 or Xq23-q24 are summarised in Fig.…”

“…The chromosomal regions corresponding to the loci IHPS3 and IHPS4 each harbour a gene from the same family of canonical transient receptor potential (TRPC) cation channels: TRPC6 on chromosome 11q21-q22 and TRPC5 on chromosome Xq23-q24. These genes represent the strongest functional candidate in each region (Everett et al 2008b). The TRPC genes have been implicated in smooth muscle hypertrophy (Dietrich et al 2006), respond to mechanical stimuli (Maroto et al 2005;Spassova et al 2006) and are widely expressed in mammalian tissue (Riccio et al 2002).…”

“…A second locus for monogenic IHPS on chromosome 16q24 has since been identiWed (IHPS5, MIM #612525) (Everett et al 2008a). Recently, we reported the results of a single nucleotide polymorphism (SNP)-based genome-wide linkage scan which demonstrated linkage to chromosomes 11q14-q22 (IHPS3, MIM #612017) and Xq23-q24 (IHPS4, MIM #300711) (Everett et al 2008b). The chromosomal regions corresponding to the loci IHPS3 and IHPS4 each harbour a gene from the same family of canonical transient receptor potential (TRPC) cation channels: TRPC6 on chromosome 11q21-q22 and TRPC5 on chromosome Xq23-q24.…”

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

“…Autosomal dominant monogenic forms of IHPS have also been reported in several extended pedigrees [16][17][18] . Five loci for familial IHPS have been identified: IHPS1 (the 5 NOS1 gene on chromosome 12q24) 19 ; IHPS2 (chromosome 16p12-p13) 16 ; IHPS3 (chromosome 11q14-q22) 20 ; IHPS4 (chromosome Xq23) 20 ; and IHPS5 (chromosome 16q24) 21 .…”

Infantile Hypertrophic Pyloric Stenosis Surgery versus Nutritional Therapy

“…Several hypotheses on pathogenesis have been suggested over the past decades, involving hormone regulation, genetic and inheritance mutations, molecular and ultrastructural abnormalities [1][2][3][4][5][6][7]. These hypotheses have not modified the treatment of IHPS, which is currently mainly surgical.…”