A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease

Paola Griseri, Barbara Pesce, Giovanna Patrone, Jan Osinga, Francesca Puppo, Monica Sancandi, Robert Hofstra, Giovanni Romeo, Roberto Ravazzolo, Marcella Devoto, Isabella Ceccherini

Research output: Contribution to journalArticlepeer-review


Hirschsprung disease (HSCR) is a common genetic disorder characterized by intestinal obstruction secondary to enteric aganglionosis. HSCR demonstrates a complex pattern of inheritance, with the RET proto-oncogene acting as a major gene and with several additional susceptibility loci related to the Ret-signaling pathway or to other developmental programs of neural crest cells. To test how the HSCR phenotype may be affected by the presence of genetic variants, we investigated the role of a single-nucleotide polymorphism (SNP), 2508C→T (S836S), in exon 14 of the RET gene, characterized by low frequency among patients with HSCR and overrepresentation in individuals affected by sporadic medullary thyroid carcinoma. Typing of several different markers across the RET gene demonstrated that a whole conserved haplotype displayed anomalous distribution and nonrandom segregation in families with HSCR. We provide genetic evidence about a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrate a possible functional effect linked to RET messenger RNA expression.

Original languageEnglish
Pages (from-to)969-974
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2002

ASJC Scopus subject areas

  • Genetics


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