Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

Anne Sophie Jannot, Jeanne Amiel, Anna Pelet, Francesca Lantieri, Raquel M. Fernandez, Joke B G M Verheij, Merce Garcia-Barcelo, Stacey Arnold, Isabella Ceccherini, Salud Borrego, Robert M W Hofstra, Paul K H Tam, Arnold Munnich, Aravinda Chakravarti, Françoise Clerget-Darpoux, Stanislas Lyonnet

Research output: Contribution to journalArticlepeer-review

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.

Original languageEnglish
Pages (from-to)917-920
Number of pages4
JournalEuropean Journal of Human Genetics
Volume20
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • Hirschsprung disease
  • parent-of-origin effect
  • parental transmission asymmetry
  • reproductive rate

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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