Genetics of recurrent pregnancy loss: a review

Abstract

Purpose of review Human reproduction is remarkably inefficient; with pregnancy loss occurring in 10–30% of clinically recognized pregnancies. Of those, 3–5% of couples experience recurrent pregnancy loss (RPL), more than 50% of who never receive an underlying diagnosis. Herein, we review evidence that genetic changes, including pathogenic variant(s) in highly penetrant genes, may provide an explanation for a proportion of couples with pregnancy loss. Recent findings Genetic abnormalities that may predispose to pregnancy loss include chromosomal aneuploidy, copy number variants, single-gene changes and others. Although previously limited by the need for hypothesis-driven assessment, advancement of various molecular technologies have sheparded in the opportunity to identify molecular cause of highly heterogeneous conditions, including RPL. The identification of causative genetic aberrations associated with RPL demonstrates a promising area of further research. Summary The journey of human development from a single-cell zygote to a term infant is complex process. Early research into copy number variants and highly penetrant single-gene changes may provide diagnosis for a proportion of couples with RPL as well as inform genes critical for early human development.

Cytogenetic Analysis of Sporadic First-Trimester Miscarriage Specimens Using Karyotyping and QF-PCR: A Retrospective Romanian Cohort Study

“…Potential genetic causes of miscarriage in euploid pregnancies include single-nucleotide variants that affect individual genes (changes in genes involved in centrosome integrity, anti-inflammatory and immune responses, cell differentiation and proliferation, blood coagulation, connective tissue, endocrine and neuromuscular systems, etc.) detectable by sequencing and submicroscopic abnormalities (inherited or de novo copy number variants involving genes associated with embryo implantation, growth and early development, immune signaling) detectable by microarray analysis [ 51 , 52 ]. The aberrant DNA methylation of several imprinted loci at genes implicated in oocyte development, maturation, skewed X chromosome inactivation, or histone modifications in placental tissue can also contribute to euploid miscarriage [ 51 , 53 ].…”

Patterns of Cytogenomic Findings from a Case Series of Recurrent Pregnancy Loss Provide Insight into the Extent of Genetic Defects Causing Miscarriages

“…9,10 Since chromosomal abnormalities represent the most common cause of pregnancy loss, a detailed analysis of the occurrence and patterns of chromosomal abnormalities in RPL could provide insight into genetic predisposition to meiotic nondisjunction and genomic instability for underlying molecular mechanisms causing miscarriages. 2,3 Cytogenetic analyses on case series of RPL and a recent meta-analysis indicated no difference in the distribution of chromosomal abnormalities between SPL and RPL but probably a significantly higher incidence of chromosomal abnormalities in SPL than in RPL. [11][12][13][14] We performed a retrospective study to evaluate the diagnostic cytogenomic findings from a single analysis (SA) group and a consecutive analysis (CA) group of a case series of RPL to compare the spectrum of cytogenomic abnormalities between the two groups and to evaluate the patterns of cytogenetic findings within the CA group.…”

“…1 Most couples go on to achieve a successful pregnancy after an SPL, but 3 to 5% of couples experience recurrent pregnancy loss (RPL). 2 Earlier data and current cytogenetic analysis detect chromosomal abnormalities, including numerical abnormalities of autosomal trisomies, monosomy X, and polyploidies, as well as structural abnormalities of various types of chromosomal imbalances, in approximately 50% of products of conception (POC). 3 4 5 The analytical validation and clinical utilization of chromosome microarray analysis (CMA) enabled the further characterization of genomic imbalances from structural rearrangements and the detection of pathogenic copy number variants (pCNVs) from POC specimens with culture failure and normal karyotypes.…”

Two novel TMEM67 variations in a Chinese family with recurrent pregnancy loss: a case report

“…Recurrent pregnancy loss (RPL) is a devastating reproductive health burden, affects about 3-5% of couples trying to conceive globally (1). The etiology of RPL is complex, involving genetic abnormalities, metabolic disorders, autoimmune diseases, and endometrial dysfunction (2,3). The causes reason of RPL are still unknown in more than 50% of these couples.…”