期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 20, 期 9, 页码 917-920出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2012.35
关键词
Hirschsprung disease; parent-of-origin effect; parental transmission asymmetry; reproductive rate
资金
- French National Research Agency (ANR)
- Fondation pour la Recherche Medicale (FRM)
- National Institutes of Health [R37 HD28088]
- Italian Telethon [GGP04257]
- Fondo de Investigacion Sanitaria, Spain [PI1001290]
- Consejeria de Economia, Innovacion y Ciencia de la Junta de Andalucia [CTS7447]
- NWO [901-04-225]
- Bernoulle Foundation
- Ubbo Emmius Foundation
- Hong Kong Research Grant Council [HKU 765407]
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. European Journal of Human Genetics (2012) 20, 917-920; doi:10.1038/ejhg.2012.35; published online 7 March 2012
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