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.

Hirschsprung disease, parent-of-origin effect, parental transmission asymmetry, reproductive rate
dx.doi.org/10.1038/ejhg.2012.35, hdl.handle.net/1765/61263
European Journal of Human Genetics
Department of Clinical Genetics

Jannot, A-S, Amiel, J, Pelet, A, Lantieri, F, Fernández, R.M, Verheij, J.B, … 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. doi:10.1038/ejhg.2012.35