TY - JOUR
T1 - Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease
AU - Jannot, Anne Sophie
AU - Amiel, Jeanne
AU - Pelet, Anna
AU - Lantieri, Francesca
AU - Fernandez, Raquel M.
AU - Verheij, Joke B.G.M.
AU - Garcia-Barcelo, Merce
AU - Arnold, Stacey
AU - Ceccherini, Isabella
AU - Borrego, Salud
AU - Hofstra, Robert M.W.
AU - Tam, Paul K.H.
AU - Munnich, Arnold
AU - Chakravarti, Aravinda
AU - Clerget-Darpoux, Françoise
AU - Lyonnet, Stanislas
N1 - Funding Information:
This study is a contribution from The International Hirschsprung Disease Consortium. We thank the numerous patients, families and referring physicians across the world who have participated in studies of Hirschsprung disease in our laboratories. This work was funded by the French National Research Agency (ANR, grants MRARE-HirGenet to SL, and ERare-HCR Consortium to SL, IC, and SB), the Fondation pour la Recherche Médicale (FRM) to SL and JA; the National Institutes of Health (R37 HD28088 to AC); the Italian Telethon (GGP04257 to IC); the Fondo de Investigación Sanitaria, Spain PI1001290 and Consejería de Economía, Innovación y Ciencia de la Junta de Andalucía (CTS7447) to SB; the NWO (901-04-225) Bernoulle Foundation and Ubbo Emmius Foundation to RMWH; and the Hong Kong Research Grant Council (HKU 765407 to MG-B and PKHT).
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Hirschsprung disease
KW - parent-of-origin effect
KW - parental transmission asymmetry
KW - reproductive rate
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U2 - 10.1038/ejhg.2012.35
DO - 10.1038/ejhg.2012.35
M3 - Article
C2 - 22395866
AN - SCOPUS:84865251825
SN - 1018-4813
VL - 20
SP - 917
EP - 920
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -