Genetic diagnosis of subfertility: the impact of meiosis and maternal effects

Abstract

During reproductive age, approximately one in seven couples are confronted with fertility problems. While the aetiology is diverse, including infections, metabolic diseases, hormonal imbalances and iatrogenic effects, it is becoming increasingly clear that genetic factors have a significant contribution. Due to the complex nature of infertility that often hints at a multifactorial cause, the search for potentially causal gene mutations in idiopathic infertile couples has remained difficult. Idiopathic infertility patients with a suspicion of an underlying genetic cause can be expected to have mutations in genes that do not readily affect general health but are only essential in certain processes connected to fertility. In this review, we specifically focus on genes involved in meiosis and maternal-effect processes, which are of critical importance for reproduction and initial embryonic development. We give an overview of genes that have already been linked to infertility in human, as well as good candidates which have been described in other organisms. Finally, we propose a phenotypic range in which we expect an optimal diagnostic yield of a meiotic/maternal-effect gene panel.

Keywords: clinical genetics; diagnostics; genetic screening/counselling; obstetrics and gynaecology.

Figure 1

Overview of critical processes during the MI stage. (A) After DNA replication, sister chromatids of both homologous chromosome pairs are held together by multiple units of the cohesin complex. (B) Alignment of the homologous chromosomes is facilitated by the synaptonemal complex. (C) The first step of homologous recombination occurs through the formation of double strand breaks (DBS). This process is Spo-11 dependent, and strand invasion is mediated by the Rad51-DMC1 complex, which is stabilised by Hop2-Mnd1. (D) After homologous recombination, the cohesin complex of the sister chromatids is cleaved by separase along the length of the sister chromatids. Cohesin at the centromeres is protected by shugosin, inhibiting the separase-mediated cleaving. (E) Sister kinetochores connect to microtubules emanating from the same spindle poles, as such separating the newly recombined homologues.

Figure 2

Overview of the general methylation and transcriptional status of the oocyte, zygote and further developmental stages. From fertilisation on, the paternal DNA is actively demethylated. Demethylation of the maternal DNA occurs more passively, being not replaced during initial cell divisions. From the blastocyst stage on, expression of DNMT1 increases, which goes together with an increase of methylation of the embryonic DNA. Transcripts originating from the oocyte are very stable and constitute most of the mRNA during initial stages. However, from the 4–8 cell stage on, embryonic transcripts take over. SC, synaptonemal complex.