Fine mapping of the 9q31 Hirschsprung's disease locus

Hum Genet. 2010 Jun;127(6):675-83. doi: 10.1007/s00439-010-0813-8. Epub 2010 Apr 2.


Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian Continental Ancestry Group / genetics
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Chromosomes, Human, Pair 9*
  • Digestive System / innervation
  • Family
  • Genome-Wide Association Study
  • Genotype
  • Hirschsprung Disease / genetics*
  • Humans
  • Mutation / genetics
  • Physical Chromosome Mapping / methods*
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins c-ret / genetics*
  • Transcriptional Elongation Factors
  • Urea Cycle Disorders, Inborn / genetics


  • Carrier Proteins
  • Elp1 protein, human
  • Transcriptional Elongation Factors
  • Proto-Oncogene Proteins c-ret