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

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.

• Authors: 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
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 20 Issue 9 Pg. 917-20 (Sep 2012) ISSN: 1476-5438 [Electronic] England
• PMID: 22395866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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