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 journalArticle

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 (US)
Pages (from-to)917-920
Number of pages4
JournalEuropean Journal of Human Genetics
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2012

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Jannot, A. S., Amiel, J., Pelet, A., Lantieri, F., Fernandez, R. M., Verheij, J. B. G. M., Garcia-Barcelo, M., Arnold, S., Ceccherini, I., Borrego, S., Hofstra, R. M. W., Tam, P. K. H., Munnich, A., Chakravarti, A., Clerget-Darpoux, F., & Lyonnet, S. (2012). Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. European Journal of Human Genetics, 20(9), 917-920. https://doi.org/10.1038/ejhg.2012.35