Identity-by-descent and association mapping of a recessive gene for hirschsprung disease on human chromosome 13q22

Erik G.puffenberger, Erick R.kauffman, Stacey Bolk, Tara C.matise, Sarah S.washington, Misha Angrist, Jean Weissenbach, Kenneth L.garver, Maria Mascari, Roger Ladda, Susan A.siaugenhaupt, Aravinda Chakravarti

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215 Scopus citations


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 genotyplng three small multlcase families and locating genomlc 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 microsatelllte 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.

Original languageEnglish (US)
Pages (from-to)1217-1225
Number of pages9
JournalHuman molecular genetics
Issue number8
StatePublished - Aug 1994

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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