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^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.