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 ~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. Methodology and Principal Findings To test whether all RET^R114H 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.