title: Recurrent triploidy due to a failure to complete maternal meiosis II: whole-exome sequencing reveals candidate variants.
abstract: Triploidy is a relatively common cause of miscarriage; however, recurrent triploidy has rarely been reported. A healthy 34-year-old woman was ascertained because of 18 consecutive miscarriages with triploidy found in all 5 karyotyped losses. Molecular results in a sixth loss were also consistent with triploidy. Genotyping of markers near the centromere on multiple chromosomes suggested that all six triploid conceptuses occurred as a result of failure to complete meiosis II (MII). The proband's mother had also experienced recurrent miscarriage, with a total of 18 miscarriages. Based on the hypothesis that an inherited autosomal-dominant maternal predisposition would explain the phenotype, whole-exome sequencing of the proband and her parents was undertaken to identify potential candidate variants. After filtering for quality and rarity, potentially damaging variants shared between the proband and her mother were identified in 47 genes. Variants in genes coding for proteins implicated in oocyte maturation, oocyte activation or polar body extrusion were then prioritized. Eight of the most promising candidate variants were confirmed by Sanger sequencing. These included a novel change in the PLCD4 gene, and a rare variant in the OSBPL5 gene, which have been implicated in oocyte activation upon fertilization and completion of MII. Several variants in genes coding proteins playing a role in oocyte maturation and early embryonic development were also identified. The genes identified may be candidates for the study in other women experiencing recurrent triploidy or recurrent IVF failure.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4 Medical Genetics, Department of Biomedicine, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Filges
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4.
authors.forename: I
authors.initials: I
authors.lastname: Manokhina
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4.
authors.forename: M S
authors.initials: MS
authors.lastname: Peñaherrera
authors.affiliation: Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4 Department of Pathology, University of British Columbia, Vancouver, BC, Canada V6T 2B5.
authors.forename: D E
authors.initials: DE
authors.lastname: McFadden
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4.
authors.forename: K
authors.initials: K
authors.lastname: Louie
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4 Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
authors.forename: E
authors.initials: E
authors.lastname: Nosova
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4.
authors.forename: J M
authors.initials: JM
authors.lastname: Friedman
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4 wrobinson@cfri.ca.
authors.forename: W P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D059786:Abnormal Karyotype; D000026:Abortion, Habitual / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000328:Adult; D059472:Exome; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008540:Meiosis; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D054803:Phospholipase C delta / Q000235:genetics; D011247:Pregnancy; D011987:Receptors, Steroid / Q000235:genetics; D017422:Sequence Analysis, DNA; D057885:Triploidy; D000098825:Oxysterol Binding Proteins
chemical_list: D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C518030:PLCD4 protein, human; D054803:Phospholipase C delta
keywords: meiosis; oogenesis; triploidy; whole-exome sequencing