title: Mosaicism and prenatal diagnosis options: insights from retinoblastoma.
abstract: In sporadic cases, a post-zygotic mutational event signifies a somatic mosaicism in the affected child only, which implies that these mutations affect only a portion of the body. Therefore siblings do not need follow-up. On the other hand, a pre-zygotic mutation transmitted by an unaffected mosaic parent implies recurrent risks in offspring. To better estimate the contribution of pre- and post-zygotic events, we analysed 124 consecutive bilateral retinoblastoma probands, carrying a heterozygous RB1 pathogenic variant and their unaffected, non-carrier parents. In order to evaluate somatic mosaicism in blood, the deleterious RB1 pathogenic variant identified in the proband, was searched for in the unaffected parents, using targeted deep sequencing. Observed recurrences, which represent an estimation of germline and somatic mosaicisms, were recorded and computed in the sibships. Deep sequencing revealed one mosaic-unaffected parent out of 124 tested couples, which provides an estimation of the maximal risk of recurrence, due to parental mosaicism, at 0.4%. Follow-up in the sibships showed one recurrence, providing a maximal recurrence risk, due to parental mosaicism, at 0.8%. Two different statistical strategies led to close estimates (0.4 and 0.8% risks) which appeared 266-533-fold higher, as compared with the general population. These recurrence estimates could be considered when counselling couples with retinoblastoma or diseases with a high de novo mutation rate.
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dehainault
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Golmard
authors.affiliation: Institut Curie, PSL Research University, 26 rue d'Ulm, Paris, France.|CNRS UMR 3244, 26 rue d'Ulm, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Gaël A
authors.initials: GA
authors.lastname: Millot
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Charpin
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Laugé
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Tarabeux
authors.affiliation: Département d'oncologie pédiatrique, adolescents jeunes adultes, Institut Curie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cassoux
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|INSERM U830, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gauthier-Villars
authors.affiliation: Service de Génétique, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|INSERM U830, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
mesh_terms: D005817:Genetic Counseling / Q000379:methods; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D009030:Mosaicism; D059645:Mutation Rate; D010290:Parents; D011296:Prenatal Diagnosis / Q000379:methods*; D012175:Retinoblastoma / Q000175:diagnosis / Q000235:genetics*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D035781:Siblings; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases