rs2435357

This fine-mapping study of the 9q31 Hirschsprung's disease (HSCR) locus identified population-specific susceptibility variants. In Dutch HSCR patients without RET coding mutations, SVEP1 SNPs rs10816998 (p=5.33×10⁻⁵, OR=2.38) and rs7038415 (p=7.50×10⁻⁵, OR=2.35) showed strong association, but failed replication. In Chinese HSCR patients, IKBKAP SNPs were associated, particularly in RET mutation carriers (rs10979596/rs10979597: p=5.10×10⁻⁶, OR=3.32), suggesting population-specific genetic architecture and epistatic interaction between RET mutations and 9q31 modifiers.

This study demonstrates a genetic interaction between the RET enhancer polymorphism rs2435357 (C>T) on chromosome 10 and chromosome 21 dosage in Down syndrome and Hirschsprung disease. The RET +9.7 T allele showed significant association with HSCR in both transmission disequilibrium (P=0.0015) and case-control (P=0.0115) analyses, with allele frequencies of 0.26 in DS alone, 0.61 in HSCR alone, and 0.41 in DS+HSCR, representing the first reported genetic interaction between a common functional variant and chromosome 21 dosage in human developmental disorders.