Linkage of Monogenic Infantile Hypertrophic Pyloric Stenosis to Chromosome 16p12-p13 and Evidence for Genetic Heterogeneity

Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is the most common form of bowel obstruction in infancy. The disease affects males four times more often than females and is considered a paradigm for the sex-modified model of multifactorial inheritance. However, pedigrees consistent with autosomal dominant inheritance have also been documented. We analyzed a 3-generation family with IHPS including 10 affected individuals (5 males and 5 females) and mapped the underlying disease locus to chromosome 16p12-p13 (LOD score 3.23) by using a single-nucleotide polymorphism-based genomewide scan. The analysis of 10 additional multiplex pedigrees yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity. Sequence analysis of candidate genes from the chromosome 16 disease interval excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.

Genome-wide linkage analysis in families with infantile hypertrophic pyloric stenosis indicates novel susceptibility loci

“…Also, two markers on chromosome 16p were added because of a recently published report of linkage in this region. 8 Average marker density of the fine-mapped regions was 2.9 cM. Mean heterozygosity for autosomal markers was 0.76, and the mean success rate for included markers was 0.80.…”

“…Two additional markers were also added to an earlier identified IHPS locus on chromosome 16p. 8 The fine mapping results of the Swedish material are plotted as red curves in Figures 2 and 3. Inclusion of the fine mapping markers enhanced the NPL score in the fine-mapped regions on chromosome 2q, 6p, 7p, 12q and 13q demonstrating NPL scores between 1.75 and 4.55 (Tables 3 and 4 the result to the Swedish material, NPL scores decreased in all regions except at the locus on 8q (green curves Figures 2 and 3).…”

“…However, this could not be replicated in any other families of same ancestry investigated, indicating locus heterogeneity of the disease. 8,9 Previously, a SNP-based genome-wide scan identified linkage to chromosome 11q14-q22 and chromosome Xq23 in a material of 81 Caucasian pedigrees. 10 IHPS is also described in association with duplication of chromosome 9q11-q33, but linkage analysis of this region did not provide evidence for an IHPS locus among 20 families with several affected IHPS cases.…”

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 .…”

“…A large Irish Caucasian family was ascertained as previously described 16 ; all affected individuals had undergone pyloromyotomy for IHPS (see Figure 1 for pedigree structure). The study was approved by the University College London Hospital Ethics Committee and relevant local regional committees.…”