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

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

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.

2012. Eur. J. Hum. Genet.; 20(9):917-920
Link to pubmed

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