Risk of Recurrent Pregnancy Loss in the Ukrainian Population Using a Combined Effect of Genetic Variants: A Case-Control Study

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

Section: Discussionmentioning

confidence: 99%

Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Gemmati

Longo

Franchini

et al. 2021

“…In this context, Barban et al [56], analyzing about 700,000 individuals, identified 12 loci associated with reproductive behavior highlighting also candidate genes and potentially causal variants [56]. Recently, Loizidou et al [57] assessed in a Ukainian cohort an association between 12 genetic loci and recurrent pregnancy loss [57]. In addition to the possibility to discover novel candidate genes and mutations, these GWASs on common genetic risk factors provide novel clues to interpret the underlying relationships and causality involved in the regulation of reproduction and fertility.…”

Section: Genetic Diseasesmentioning

confidence: 99%

Unraveling the Balance between Genes, Microbes, Lifestyle and the Environment to Improve Healthy Reproduction

D’Argenio

Dittfeld²,

Lazzeri³

et al. 2021

Humans’ health is the result of a complex and balanced interplay between genetic factors, environmental stimuli, lifestyle habits, and the microbiota composition. The knowledge about their single contributions, as well as the complex network linking each to the others, is pivotal to understand the mechanisms underlying the onset of many diseases and can provide key information for their prevention, diagnosis and therapy. This applies also to reproduction. Reproduction, involving almost 10% of our genetic code, is one of the most critical human’s functions and is a key element to assess the well-being of a population. The last decades revealed a progressive decline of reproductive outcomes worldwide. As a consequence, there is a growing interest in unveiling the role of the different factors involved in human reproduction and great efforts have been carried out to improve its outcomes. As for many other diseases, it is now clear that the interplay between the underlying genetics, our commensal microbiome, the lifestyle habits and the environment we live in can either exacerbate the outcome or mitigate the adverse effects. Here, we aim to analyze how each of these factors contribute to reproduction highlighting their individual contribution and providing supporting evidence of how to modify their impact and overall contribution to a healthy reproductive status.

“…Genetics now play an essential role in all stages of the reproductive path, from the diagnostic approach to the choice of more complex therapies: numerous research advances in genetics have increased reproductive medicine's success. For example, the rapid progress of the technologies applied to molecular diagnosis provides several diagnostic and screening options for the identification of genetic and chromosomal alterations related to infertility [1], non-syndromic infertility [2] or recurrent pregnancy loss [3]. However, while female infertility has been extensively investigated, only recently, attention is being paid to the etiological and pathophysiological causes related to male infertility.…”

mentioning

confidence: 99%

Genetics and Genomics of Reproductive Medicine

Tomaiuolo

2021