Potential genetic causes of miscarriage in euploid pregnancies: a systematic review

Abstract

BACKGROUND Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized. OBJECTIVE AND RATIONALE The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss. SEARCH METHODS A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms ‘spontaneous abortion’, ‘miscarriage’, ‘pregnancy loss’, or ‘lethal’ were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including ‘exome’, ‘human genome’, ‘sequencing analysis’, ‘sequencing’, ‘copy number variation’, ‘single-nucleotide polymorphism’, ‘microarray analysis’, and ‘comparative genomic hybridization’. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle–Ottawa scale. OUTCOMES A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage. WIDER IMPLICATIONS Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

“…In principle, a new L1 insertion into a lethal gene could initiate a cascade leading to fetal death, although our diploid nature limits such consequences. Many signaling pathways and genes are involved in the process of miscarriage and single gene mutations may cause spontaneous abortion [6]. Based on a study of 489 single gene knockout mouse models, White et al [88] found 29 percent of the genes to be lethal and 13 percent sublethal.…”

“…KIF7 (kinesin family member gene 7) was the first human gene associated with fetal lethality when it was found to cause hydrolethalus and acrocallosal syndromes [89], and since then many other candidate genes have been identified. A review of 50 human studies identified a range of possible causative gene and copy number variations (CNVs) for miscarriage, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were reported by multiple studies [6]. Several whole exome sequence analyses of euploid miscarriages have been conducted, including a study of 30 fetuses in which mutations in FGFR3 (fibroblast growth factor receptor 3), COL2A1 (collagen, type II, alpha 1), and OFD1 (oral-facial-digital syndrome 1) genes, in addition to structural variants, accounted for 10 percent of the cohort [90].…”

“…Abnormal chromosome karyotype is seen in about 50% of spontaneous abortion patients, with triploidy most common, followed by autosomal unbalanced translocation, and polyploidy, X monomer, autosomal monomer, chromosome balanced translocation, deletion, chimerism, inversion, overlap, and so on [4,5]. During embryonic development a single lethal gene mutation may also lead to death of the embryo [6]. Furthermore, evidence suggests that epigenetic anomalies may lie behind some cases of early pregnancy loss [7].…”

Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion

“…The villi of RSA patients and elective pregnancy termination patients were collected, and the tissues' volume were generally not more than 1mm 3 . Fresh tissues were quickly placed into the electron microscope fixative (Servicebio), fixed at 4 °C for 2-4 h, and post-fixed in 1% osmium acid for 2h.…”

Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion

“…The villi of RSA patients and normal abortion patients were collected, and the tissues' volume were generally not more than 1mm 3 . Fresh tissues were quickly placed into the electron microscope fixative (Servicebio), fixed at 4 °C for 2-4 h, and post-fixed in 1% osmium acid for 2 h. The samples were dehydrated in a series of gradient concentration alcohols, permeated overnight with a mixture of acetone and 812 embedding agent (SPI) (2:1), then embedded in pure 812 embedding agent and polymerized in a 60 °C oven for 48 h. Samples were cut into 60-80 nm ultrathin sections by using ultrathin slicing machine (Leica UC7).…”