title: 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.affiliation: INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jannot
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernandez
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.forename: Merce
authors.initials: M
authors.lastname: Garcia-Barcelo
authors.forename: Stacey
authors.initials: S
authors.lastname: Arnold
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Françoise
authors.initials: F
authors.lastname: Clerget-Darpoux
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000483:Alleles; D005260:Female; D005787:Gene Frequency; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D059645:Mutation Rate; D016366:Open Reading Frames; D010375:Pedigree; D019683:Penetrance; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012098:Reproduction / Q000235:genetics*; D012737:Sex Factors; D035781:Siblings
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human