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.

Figure 1.

The three multigeneration IHPS pedigrees. Biological samples were obtained from all living individuals, except those marked with an asterisk (*). No samples were obtained from any of the deceased family members. Question marks (?) indicate individuals whose disease status could not be determined.

Figure 2.

Mapping of the IHPS disease locus to chromosome 16p. A, Output of chromosome 16 multipoint LOD score analysis. B, Definition of the disease interval by means of haplotype analysis. The middle row (Founder) shows the SNP haplotype segregating in the affected individuals from family IHPS036. The top and bottom rows show the recombining haplotypes observed in subjects 36.206 and 36.301. Arrows indicate the sites of recombination, and the genomic segment shared by all affected individuals is underlined.