Mapping of a Hirschsprung's disease locus in 3p21.
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.
Garcia-Barceló
Maria-Mercè
MM
Department of Surgery, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China. paultam@hkucc.hku.hk
Fong
Pui-yee
PY
Tang
Clara S
CS
Miao
Xiao-ping
XP
So
Man-ting
MT
Yuan
Zhen-wei
ZW
Li
Long
L
Guo
Wei-hong
WH
Liu
Lei
L
Wang
Bin
B
Sun
Xiao-Bing
XB
Huang
Liu-Ming
LM
Tou
Jin-Fa
JF
Wong
Kenneth Kak-Yuen
KK
Ngan
Elly Sau-Wai
ES
Lui
Vincent Chi-hang
VC
Cherny
Stacey S
SS
Sham
Pak-chung
PC
Tam
Paul Kwong-hang
PK
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
D005819:Genetic Markers