Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

Grzegorz M. Burzynski, Ilja M. Nolte, Jan Osinga, Isabella Ceccherini, Bas Twigt, Saskia Maas, Alice Brooks, Joke Verheij, Ivan Plaza Menacho, Charles H C M Buys, Robert M W Hofstra

Research output: Contribution to journalArticlepeer-review

Abstract

Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5′ region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR>20). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.

Original languageEnglish
Pages (from-to)604-612
Number of pages9
JournalEuropean Journal of Human Genetics
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 2004

Keywords

  • Haplotype reconstruction
  • Hirschsprung disease
  • HSCR
  • RET

ASJC Scopus subject areas

  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2'. Together they form a unique fingerprint.

Cite this