title: Mapping of a Hirschsprung's disease locus in 3p21.
abstract: Hirschsprung's disease (HSCR) is a congenital disorder in which ganglion cells are absent in variable portions of the lower digestive tract according to which patients are classified. The RET gene is the major HSCR gene, although reduced penetrance of RET mutations and variable expression of HSCR phenotype indicates that more than one gene is required. An unidentified RET-dependent modifier on 3p21 appears to be necessary for transmission of the short HSCR (S-HSCR) phenotype. We investigated 6 Mb of the 3p21 region on a quest for the HSCR-susceptibility locus. Fifty-eight S-HSCR case-parent trios were genotyped using Sequenom technology for 214 tag single nucleotide polymorphisms (SNPs) distributed along 6 Mb of the 3p21 region. A five-marker haplotype, spanning a 118 kb gene-rich region, was found to be overtransmitted to affected offspring. The associated haplotype encompasses three genes involved in neurological phenotypes. Importantly, this association was replicated in an independent sample of 172 S-HSCR cases and 153 unrelated controls. Ranking markers by proximity to candidate genes or by expected functional consequences could be used in follow-up studies to finally pinpoint this HSCR locus.
authors.affiliation: Department of Surgery, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China. paultam@hkucc.hku.hk
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
authors.forename: Pui-yee
authors.initials: PY
authors.lastname: Fong
authors.forename: Clara S
authors.initials: CS
authors.lastname: Tang
authors.forename: Xiao-ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Man-ting
authors.initials: MT
authors.lastname: So
authors.forename: Zhen-wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Wei-hong
authors.initials: WH
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Sun
authors.forename: Liu-Ming
authors.initials: LM
authors.lastname: Huang
authors.forename: Jin-Fa
authors.initials: JF
authors.lastname: Tou
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Vincent Chi-hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Pak-chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Paul Kwong-hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005190:Family; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011786:Quality Control
chemical_list: D005819:Genetic Markers