title: Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22.
abstract: Hirschsprung disease (HSCR) is a congenital disorder of unknown etiology characterized by the absence of enteric ganglia in the distal colon. We have ascertained a large, inbred, Mennonite kindred which demonstrates a high incidence of Hirschsprung disease (HSCR). Genealogical analysis of all kinship relationships identified a single common ancestral couple for all parents of affected offspring. Segregation analysis yielded a segregation ratio of 10.67% for males and 5.45% for females. We searched for locations of the gene(s) responsible for HSCR in this pedigree by genotyping three small multicase families and locating genomic regions demonstrating identity-by-descent followed by linkage disequilibrium analysis of 28 additional nuclear families. Based on this novel strategy, we report the mapping of a new locus for HSCR to chromosome 13q22. Nine microsatellite markers spanning 10 cM in this region were genotyped on thirty-one nuclear families. Significant nonrandom association was detected with alleles at markers D13S162, D13S160, D13S170, and AFM240zg9. In addition, our studies reveal preliminary evidence for a genetic modifier of HSCR in this kindred on chromosome 21q22.
authors.affiliation: Department of Human Genetics, University of Pittsburgh, PA 15261.
authors.forename: E G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: E R
authors.initials: ER
authors.lastname: Kauffman
authors.forename: S
authors.initials: S
authors.lastname: Bolk
authors.forename: T C
authors.initials: TC
authors.lastname: Matise
authors.forename: S S
authors.initials: SS
authors.lastname: Washington
authors.forename: M
authors.initials: M
authors.lastname: Angrist
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: K L
authors.initials: KL
authors.lastname: Garver
authors.forename: M
authors.initials: M
authors.lastname: Mascari
authors.forename: R
authors.initials: R
authors.lastname: Ladda
mesh_terms: D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree