title: Germline mosaicism is a pitfall in PGD for X-linked disorders. Single sperm typing detects very low frequency paternal gonadal mosaicism in a case of recurrent chondrodysplasia punctata misattributed to a maternal origin.
abstract: This manuscript presents a molecularly demonstrated gonadal mosaicism from paternal origin for X-linked dominant chondrodysplasia punctata by single sperm typing. A couple who had experienced two medical terminations of pregnancy of female fetuses was referred to our pre-implantation genetic diagnosis (PGD) centre with the diagnosis of maternally derived gonadal mosaicism. Indeed, genetic analyses of different DNA samples - including semen - from the healthy parents failed to detect the variant found in the fetuses. Six embryos, all male, were obtained during the PGD cycle. The causative variant was not detected in any embryo, whereas five embryos had inherited the 'at-risk' maternal haplotype. The assumption of a maternal gonadal mosaicism was still possible, but this finding allowed us to consider the possibility of a paternal rather than maternal gonadal mosaicism. It prompted us to perform extensive single sperm analyses, demonstrating a low-frequency paternal germline mosaicism, which led to completely different haplotype phasing and PGD counselling. In conclusion, this case further exemplifies that germline mosaicism is a pitfall in PGD where diagnosis largely relies on linkage analysis and suggests that tracing the parental inheritance through polar body analysis and/or single sperm typing experiments is of major importance for adequate genetic counselling and accurate PGD. © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Laboratoire de Génétique Moléculaire, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Victoria
authors.initials: V
authors.lastname: Viart
authors.affiliation: Département de Génétique Clinique, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Willems
authors.affiliation: Laboratoire de Génétique Moléculaire, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Aliya
authors.initials: A
authors.lastname: Ishmukhametova
authors.affiliation: Laboratoire de Génétique (LCBGM), Hôpital St Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dufernez
authors.affiliation: Département de Gynécologie Obstétrique, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Tal
authors.initials: T
authors.lastname: Anahory
authors.affiliation: Université de Montpellier, Montpellier, France.|Département de Biologie de la Reproduction et du Développement, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Samir
authors.initials: S
authors.lastname: Hamamah
authors.affiliation: Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHRU de Nantes, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Laboratoire de Génétique Moléculaire, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.affiliation: Laboratoire de Génétique Moléculaire, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Girardet
mesh_terms: D000328:Adult; D002806:Chondrodysplasia Punctata / Q000175:diagnosis* / Q000235:genetics; D003951:Diagnostic Errors; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis* / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D005854:Germ Cells; D006801:Humans; D008297:Male; D000072741:Maternal Inheritance / Q000235:genetics; D009030:Mosaicism; D000072740:Paternal Inheritance / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D019836:Preimplantation Diagnosis / Q000379:methods / Q000592:standards; D012008:Recurrence; D059010:Single-Cell Analysis / Q000379:methods*; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*