A RET founder mutation in Chinese hirschsprung's patients

Abstract

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. Rearranged during transfection (RET) gene is implicated in HSCR and is the major gene of this gastrointestinal disease. To date, over 200 low frequency recurrent RET coding sequence (CDS) mutations have been identified in HSCR patients. However, a highly recurrent RET(R114H) mutation has been identified in 10% of the Chinese HSCR patients which has never been found in Caucasians patients or controls nor in 400 Chinese controls. The high frequency of RET(R114H) in our population together with the fact that it is not a “de novo” mutation in the context of the most HSCR-associated RET-haplotype, suggests that it may be a founder HSCR mutation in the Chinese population. Initial investigation involved applying a Bayesian method to 21 single nucleotide polymorphisms (SNPs; across a 62kb region of RET) genotyped in 421 Chinese HSCR patients (of which 24 individuals had the mutation) to predict the approximate age of RET(R114H). The approach allowed the inference of the mutation age based on the observed linkage disequilibrium (LD) at multiple SNPs which predicted the mutation to be between 12 and 13 generations old. Including SNPs from a recently obtained genome-wide 500K dataset for 181 of the above mentioned patients (which now only included 14 patients who had the RET(R114H) mutation), we applied haplotype estimation methods to determine whether there were any segments shared between patients with the RET(R114H) compared to those without the mutation and controls. Data consisted a total of 92 SNPs spanning a 510kb region over the RET gene. Analysis yielded a 256kb (76 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients or controls. This suggests that RET(R114H) is a possible founder effect for Hirschsprung’s disease in the Chinese population.