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

Eur J Hum Genet. 2012 Sep;20(9):917-20. doi: 10.1038/ejhg.2012.35. Epub 2012 Mar 7.


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.

Publication types

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

MeSH terms

  • Alleles
  • Female
  • Gene Frequency
  • Hirschsprung Disease / genetics*
  • Humans
  • Inheritance Patterns*
  • Male
  • Mutation Rate
  • Open Reading Frames
  • Pedigree
  • Penetrance
  • Proto-Oncogene Proteins c-ret / genetics*
  • Reproduction / genetics*
  • Sex Factors
  • Siblings


  • Proto-Oncogene Proteins c-ret
  • RET protein, human