Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22.
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.
Puffenberger
E G
EG
Department of Human Genetics, University of Pittsburgh, PA 15261.
Kauffman
E R
ER
Bolk
S
S
Matise
T C
TC
Washington
S S
SS
Angrist
M
M
Weissenbach
J
J
Garver
K L
KL
Mascari
M
M
Ladda
R
R
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