Haplotype analysis reveals a possible founder effect of RET mutation R114H for Hirschsprung's disease in the Chinese population.
BACKGROUND
Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RET(R114H)) has recently been identified in approximately 6-7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RET(R114H) in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population.


RESULTS
To test whether all RET(R114) were originated from a single mutational event, we predicted the approximate age of RET(R114H) by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4-23 generations old depending on growth rate. We reasoned that if RET(R114H) was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RET(R114H) patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RET(R114H) that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients.


CONCLUSIONS
This suggests that RET(R114H) is a founder mutation for HSCR in the Chinese population.
Paediatric Surgery Division, Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, People's Republic of China.
Belinda K
BK
Cornes
Clara S
CS
Tang
Thomas Y Y
TY
Leon
Kenneth J W S
KJ
Hui
Man-Ting
MT
So
Xiaoping
X
Miao
Stacey S
SS
Cherny
Pak C
PC
Sham
Paul K H
PK
Tam
Maria-Merce
MM
Garcia-Barcelo
D016022:Case-Control Studies; D002681:China; D018703:Founder Effect; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human