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.

Molecular and histological characteristics of early triploid and partial molar pregnancies

“…In that particular study, the majority of diandric triploids had developmental ages in excess of 8.5 weeks, whereas most of the digynic triploids have aborted earlier, before developmental age 8.5 weeks, and this difference in distribution was highly significant. Other authors also found a predominance of paternal triploidy over maternal, but the cases examined were in the [11][12][13][14] th week of pregnancy [14]. On the other hand, McFadden et al (2006) reported higher incidence of digynic triploidy, but their series, the same as ours, evaluated early spontaneous abortions [15].…”

“…Digynic triploidy may be the result of fertilisation of a diploid ovum by a single sperm, with the diploid ovum being the result of an error in either the first (MI) or second (MII) meiotic division [11]. Whatever the origin of the extra chro- , who analysed 14 cases of triploidy, virtually all triploids are a consequence of an error in the ovum: either a division error leading to digyny or an abnormality of the ovum that fails to block fertilisation by more than one sperm [11,12].…”

A 92,XXXY Miscarriage Consecutive to a Digynic Triploid Pregnancy

“…Maternal NLPR7 mutations were also involved in a few cases of diandric triploidies including 1 case of recurrent triploidy [Slim et al, 2011]. Recurrent digynic triploidy is more infrequent; to our knowledge, it has been reported in 5 cases [Pergament et al, 2000;BarAmi et al 2003;Brancati et al, 2003;Huang et al, 2004;Filges et al, 2015], although not in all triploid pregnancies a molecular investigation was performed. We are not aware of other cases with combination of a digynic triploidy and a zygotic tetraploidy with a PPMM contribution.…”

Triploidy that escaped diagnosis using chromosomal microarray testing in early pregnancy loss: Two cases and a literature review

“…Unlike most chromosomal abnormalities, increased maternal age is not a risk factor for digynic or diandric triploidy. However, there have been several reports of recurrent (≥3 times) triploidy [16][17][18], and one study examined possible genetic vari-ants responsible for this phenotype [19]. These reports support the need for chromosome diagnosis in early pregnancy loss.…”