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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 March 2021) | Viewed by 51373

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Prof. Dr. Rossella Tomaiuolo

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Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
Interests: genetic tests; reproductive medicine; male infertility; female infertility; antenatal diagnosis; preimplantation diagnosis; prenatal diagnosis (PND); non-invasive prenatal screening (NIPT); antenatal age

Special Issue Information

Dear Colleagues,

Numerous research advances in the field of genetics have increased the success of reproductive medicine. Genetics now play an essential role in all stages of the reproductive path, from the diagnostic approach to the choice of more complex therapies. For example, the rapid progress of the technologies applied to laboratory diagnostics provides several diagnostic and screening options for the identification of genetic diseases and chromosomal alterations during the antenatal stage; the options now available range from non-invasive prenatal screening (NIPT) to targeted assessment of at-risk couples.

In this scenario, Genes has decided to dedicate a Special Issue in 2021 to the role of genetics and genomics in reproductive medicine to help with the creation of experimental and methodological efforts to support harmonization and improvement of the outcomes in this important field.

The intent of the Special Issue is to encourage the standardization of the diagnostic and operational processes of genetic laboratories and to characterize and discuss the use and impact of new discoveries in the field of reproductive medicine. We invite you to take part in this Special Issue with a scientific contribution. The manuscripts will, as always, be subjected to examination by specialized reviewers to guarantee their scientific acceptability.

Prof. Rossella Tomaiuolo
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

genetic tests
reproductive medicine
male infertility
female infertility
antenatal diagnosis
preimplantation diagnosis
prenatal diagnosis (PND)
non-invasive prenatal screening (NIPT)
antenatal age

Published Papers (13 papers)

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Editorial

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2 pages, 154 KiB

Open AccessEditorial

Genetics and Genomics of Reproductive Medicine

by Rossella Tomaiuolo

Genes 2021, 12(10), 1612; https://doi.org/10.3390/genes12101612 - 14 Oct 2021

Viewed by 1378

Abstract

The rapidity of innovations has meant that reproductive medicine today represents clear example of how complex but essential an adaptation of clinical practice and laboratory techniques to new knowledge is in the context of the dynamic evolution of medicine [...] Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

Research

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21 pages, 3477 KiB

Open AccessArticle

Pilot Screening of Cell-Free mtDNA in NIPT: Quality Control, Variant Calling, and Haplogroup Determination

by Alisa Morshneva, Polina Kozyulina, Elena Vashukova, Olga Tarasenko, Natalia Dvoynova, Anastasia Chentsova, Olga Talantova, Alexander Koroteev, Dmitrii Ivanov, Elena Serebryakova, Tatyana Ivashchenko, Aitalina Sukhomyasova, Nadezhda Maksimova, Olesya Bespalova, Igor Kogan, Vladislav Baranov and Andrey Glotov

Genes 2021, 12(5), 743; https://doi.org/10.3390/genes12050743 - 14 May 2021

Cited by 6 | Viewed by 3403

Abstract

Clinical tests based on whole-genome sequencing are generally focused on a single task approach, testing one or several parameters, although whole-genome sequencing (WGS) provides us with large data sets that can be used for many supportive analyses. In spite of low genome coverage, data of WGS-based non-invasive prenatal testing (NIPT) contain fully sequenced mitochondrial DNA (mtDNA). This mtDNA can be used for variant calling, ancestry analysis, population studies and other approaches that extend NIPT functionality. In this study, we analyse mtDNA pool from 645 cell-free DNA (cfDNA) samples of pregnant women from different regions of Russia, explore the effects of transportation and storing conditions on mtDNA content, analyse effects, frequency and location of mitochondrial variants called from samples and perform haplogroup analysis, revealing the most common mitochondrial superclades. We have shown that, despite the relatively low sequencing depth of unamplified mtDNA from cfDNA samples, the mtDNA analysis in these samples is still an informative instrument suitable for research and screening purposes. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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12 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Microbiological Evaluation and Sperm DNA Fragmentation in Semen Samples of Patients Undergoing Fertility Investigation

by Chiara Pagliuca, Federica Cariati, Francesca Bagnulo, Elena Scaglione, Consolata Carotenuto, Fabrizio Farina, Valeria D’Argenio, Francesca Carraturo, Paola D’Aprile, Mariateresa Vitiello, Ida Strina, Carlo Alviggi, Roberta Colicchio, Rossella Tomaiuolo and Paola Salvatore

Genes 2021, 12(5), 654; https://doi.org/10.3390/genes12050654 - 27 Apr 2021

Cited by 22 | Viewed by 2661

Abstract

Fifteen percent of male infertility is associated with urogenital infections; several pathogens are able to alter the testicular and accessory glands’ microenvironment, resulting in the impairment of biofunctional sperm parameters. The purpose of this study was to assess the influence of urogenital infections on the quality of 53 human semen samples through standard analysis, microbiological evaluation, and molecular characterization of sperm DNA damage. The results showed a significant correlation between infected status and semen volume, sperm concentration, and motility. Moreover, a high risk of fragmented sperm DNA was demonstrated in the altered semen samples. Urogenital infections are often asymptomatic and thus an in-depth evaluation of the seminal sample can allow for both the diagnosis and therapy of infections while providing more indicators for male infertility management. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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9 pages, 766 KiB

Open AccessArticle

TERRA: A Novel Biomarker of Embryo Quality and Art Outcome

by Maria Santa Rocca, Ludovica Dusi, Andrea Di Nisio, Erminia Alviggi, Benedetta Iussig, Sara Bertelle, Luca De Toni, Andrea Garolla, Carlo Foresta and Alberto Ferlin

Genes 2021, 12(4), 475; https://doi.org/10.3390/genes12040475 - 25 Mar 2021

Cited by 14 | Viewed by 1941

Abstract

Telomeres are considered to be an internal biological clock, and their progressive shortening has been associated with the risk of age-related diseases and reproductive alterations. Over recent years, an increasing number of studies have focused on the association between telomere length and fertility, identifying sperm telomere length (STL) as a novel biomarker of male fertility. Although typically considered to be repeated DNA sequences, telomeres have recently been shown to also include a long non-coding RNA (lncRNA) known as TERRA (telomeric repeat-containing RNAs). Interestingly, males with idiopathic infertility show reduced testicular TERRA expression, suggesting a link between TERRA and male fertility. The aim of this study was to investigate the role of seminal TERRA expression in embryo quality. To this end, STL and TERRA expression were quantified by Real Time qPCR in the semen of 35 men who underwent assisted reproductive technologies (ART) and 30 fertile men. We found that TERRA expression in semen and STL was reduced in patients that underwent ART (both p < 0.001). Interestingly, TERRA and STL expressions were positively correlated (p = 0.010), and TERRA expression was positively associated with embryo quality (p < 0.001). These preliminary findings suggest a role for TERRA in the maintenance of sperm telomere integrity during gametogenesis, and for the first time, TERRA expression was found as a predictive factor for embryo quality in the setting of assisted reproduction. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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15 pages, 1886 KiB

Open AccessArticle

Evaluation of a Custom Design Gene Panel as a Diagnostic Tool for Human Non-Syndromic Infertility

by Ozlem Okutman, Julien Tarabeux, Jean Muller and Stéphane Viville

Genes 2021, 12(3), 410; https://doi.org/10.3390/genes12030410 - 12 Mar 2021

Cited by 6 | Viewed by 2652

Abstract

Infertility is a global healthcare problem, which affects men and women equally. With the advance of genome-wide analysis, an increasing list of human genes involved in infertility is now available. In order to evaluate the diagnostic interest to analyze these genes, we have designed a gene panel allowing the analysis of 51 genes involved in non-syndromic human infertility. In this initial evaluation study, a cohort of 94 non-syndromic infertility cases with a well-defined infertility phenotype was examined. Five patients with previously known mutations were used as positive controls. With a mean coverage of 457×, and 99.8% of target bases successfully sequenced with a depth coverage over 30×, we prove the robustness and the quality of our panel. In total, we identified pathogenic or likely pathogenic variations in eight patients (five male and three female). With a diagnostic yield of 8.5% and the identification of a variety of variants including substitution, insertion, deletion, and copy number variations, our results demonstrate the usefulness of such a strategy, as well as the efficiency and the quality of this diagnostic gene panel. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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11 pages, 411 KiB

Open AccessArticle

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

by Eleni M. Loizidou, Anastasia Kucherenko, Pavlo Tatarskyy, Sergey Chernushyn, Ganna Livshyts, Roman Gulkovskyi, Iryna Vorobiova, Yurii Antipkin, Oleksandra Gorodna, Marika A. Kaakinen, Inga Prokopenko and Ludmila Livshits

Genes 2021, 12(1), 64; https://doi.org/10.3390/genes12010064 - 05 Jan 2021

Cited by 6 | Viewed by 2745

Abstract

We assessed the predictive ability of a combined genetic variant panel for the risk of recurrent pregnancy loss (RPL) through a case-control study. Our study sample was from Ukraine and included 114 cases with idiopathic RPL and 106 controls without any pregnancy losses/complications and with at least one healthy child. We genotyped variants within 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood coagulation (F2, F5, F7, GP1A), hormonal regulation (ESR1, ADRB2), endometrium and placental function (ENOS, ACE), folate metabolism (MTHFR) and inflammatory response (IL6, IL8, IL10). We showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased risk of RPL (odds ratio 1.56, 95% CI: 1.21, 2.04, p = 8.7 × 10⁻⁴). The receiver operator characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an improved ability of the GRS to classify women with and without RPL. Ιmplementation of the GRS approach can help define women at higher risk of complex multifactorial conditions such as RPL. Future well-powered genome-wide association studies will help in dissecting biological pathways previously unknown for RPL and further improve the identification of women with RPL susceptibility. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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12 pages, 2055 KiB

Open AccessArticle

One4Two^®: An Integrated Molecular Approach to Optimize Infertile Couples’ Journey

by Valeria D’Argenio, Federica Cariati and Rossella Tomaiuolo

Genes 2021, 12(1), 60; https://doi.org/10.3390/genes12010060 - 02 Jan 2021

Cited by 9 | Viewed by 2133

Abstract

The current diagnostic path of infertile couples is long lasting and often ineffective. Genetic tests, in particular, appear as a limiting step due to their jeopardized use on one side, and to the limited number of genes evaluated on the other. In this context, the development and diffusion, also in routine diagnostic settings, of next generation sequencing (NGS)-based methods for the analyses of several genes in multiple subjects at a time is improving the diagnostic sensitivity of molecular analyses. Thus, we developed One4Two^®, a custom NGS panel to optimize the diagnostic journey of infertile couples. The panel validation was carried out in three steps analyzing a total of 83 subjects. Interestingly, all the previously identified variants were confirmed, assessing the analytic sensitivity of the method. Moreover, additional pathogenic variants have been identified underlying the diagnostic efficacy of the proposed method. One4Two^® allows the simultaneous analysis of infertility-related genes, disease-genes of common inherited diseases, and of polymorphisms related to therapy outcome. Thus, One4Two^® is able to improve the diagnostic journey of infertile couples by simplifying the whole process not only for patients, but also for laboratories and reproduction specialists moving toward an even more personalized medicine. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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18 pages, 1475 KiB

Open AccessArticle

Age and Serum AMH and FSH Levels as Predictors of the Number of Oocytes Retrieved from Chromosomal Translocation Carriers after Controlled Ovarian Hyperstimulation: Applicability and Limitations

by Yulia V. Shilenkova, Anna A. Pendina, Irina D. Mekina, Olga A. Efimova, Evgeniia M. Komarova, Elena A. Lesik, Mariia A. Ishchuk, Elena M. Fedorova, Olga G. Chiryaeva, Lubov’ I. Petrova, Vera S. Dudkina, Olga E. Talantova, Alexander M. Gzgzyan and Igor Yu. Kogan

Genes 2021, 12(1), 18; https://doi.org/10.3390/genes12010018 - 25 Dec 2020

Cited by 3 | Viewed by 2043

Abstract

We studied the impact of age and the serum anti-Müllerian hormone (AMH)/follicle-stimulating hormone (FSH) levels on the number of cumulus–oocyte complexes (COCs) retrieved from female reciprocal and Robertsonian translocation carriers after controlled ovarian hyperstimulation (COH). The number of COCs retrieved after COH was retrospectively analyzed in female translocation carriers and 46,XX partners of male translocation carriers from 100 couples. The median number of COCs varied from nine to 16 and did not differ among subgroups of women categorized by age, presence and type of a translocation. The number of COCs correlated negatively with the woman’s age in both the reciprocal and the Robertsonian translocation carriers, while in 46,XX women no correlation was detected. The number of COCs did not differ between the reciprocal and the Robertsonian translocation carriers aged either <35 or ≥35 years. In translocation carriers, the number of COCs correlated with the serum AMH level only in the younger-age subgroups; the correlation was strong positive in reciprocal and moderate positive in Robertsonian translocation carriers. The 46,XX women aged both <35 and ≥35 years showed similar moderate positive correlations. Across all subgroups, the number of COCs correlated moderately negatively with the serum FSH level only in Robertsonian translocation carriers aged <35 years. Our results suggest that chromosomal translocations per se do not increase the risk of poor oocyte retrieval outcome after COH. In translocation carriers, oocyte retrieval outcome depends to a large extent on their age. The serum AMH level strongly predicts oocyte retrieval outcomes only in young reciprocal translocation carriers, while the serum FSH level has a moderate predictive value in young Robertsonian translocation carriers. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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17 pages, 3058 KiB

Open AccessArticle

The Pregnancy Outcome of Mosaic Embryo Transfer: A Prospective Multicenter Study and Meta-Analysis

by Ying Xin Zhang, Jang Jih Chen, Sunanta Nabu, Queenie Sum Yee Yeung, Ying Li, Jia Hui Tan, Wanwisa Suksalak, Sujin Chanchamroen, Wiwat Quangkananurug, Pak Seng Wong, Jacqueline Pui Wah Chung and Kwong Wai Choy

Genes 2020, 11(9), 973; https://doi.org/10.3390/genes11090973 - 21 Aug 2020

Cited by 46 | Viewed by 8997

Abstract

Chromosomal mosaicism is at high occurrence in early developmental-stage embryos, but much lower in those at prenatal stage. Recent studies provided evidence on the viability of mosaic embryos by reporting pregnancy outcomes. Expanded research is warranted to evaluate its clinical significance. This is a multi-center prospective cohort study on 137 mosaic, 476 euploid and 835 non-preimplantation genetic testing (non-PGT) embryos from three in vitro fertilization (IVF) providers of three countries in Asia, applying the same preimplantation genetic testing for aneuploidies (PGT-A) reporting criteria. Mosaic embryo transfers (METs) resulted in a significantly lower clinical pregnancy rate (40.1% versus 59.0% versus 48.4%), lower ongoing/live birth rate (27.1% versus 47.0% versus 35.1%) and higher miscarriage rate (33.3% versus 20.5% versus 27.4%) than euploid and non-PGT transfers, respectively. Pregnancy losses after METs were different between embryos carrying numerical and segmental chromosomal abnormalities (p = 0.04). Our meta-analysis concluded that METs gave rise to pregnancies but were associated with a reduced ongoing/live birth rate and a higher miscarriage rate. All 37 MET live births were confirmed viable, among which 8 completed prenatal genetic testing with normal results. Longitudinal investigation on one MET pregnancy evidenced the aneuploidy depletion hypothesis. This is the first multi-center prospective study reporting a full MET pregnancy outcome with complementary information from prenatal genetic testing as compared to euploid and non-PGT cohorts. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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13 pages, 695 KiB

Open AccessArticle

Association between Platelet-Specific Collagen Receptor Glycoprotein 6 Gene Variants, Selected Biomarkers, and Recurrent Pregnancy Loss in Korean Women

by Hui Jeong An, Eun Hee Ahn, Jung Oh Kim, Chang Soo Ryu, Han Sung Park, Sung Hwan Cho, Ji Hyang Kim, Woo Sik Lee, Jung Ryeol Lee, Young Ran Kim and Nam Keun Kim

Genes 2020, 11(8), 862; https://doi.org/10.3390/genes11080862 - 29 Jul 2020

Cited by 1 | Viewed by 2066

Abstract

This paper investigates whether glycoprotein 6 (GP6) gene polymorphisms are a risk factor for recurrent pregnancy loss (RPL) in Korean women. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and real-time polymerase chain reaction amplification. We identified five polymorphisms in the GP6 gene: rs1654410 T>C, rs1671153 T>G, rs1654419 G>A, rs12610286 A>G, and rs1654431 G>A. GP6 rs1654410 CC was associated with decreased RPL risk (adjusted odds ratio = 0.292, 95% confidence interval = 0.105–0.815, p = 0.019), and recessive genotypes were also significantly associated with decreased RPL risk (adjusted odds ratio = 0.348, 95% confidence interval = 0.128−0.944, p = 0.038). GP6 rs1654419 GA was associated with decreased RPL risk (adjusted odds ratio = 0.607, 95% confidence interval = 0.375-0.982, p = 0.042), and dominant genotypes were significantly associated with decreased RPL risk (adjusted odds ratio = 0.563, 95% confidence interval = 0.358−0.885, p = 0.013). Altogether, the genotype frequencies of GP6 rs1654410 T>C and GP6 rs1654419 G>A were significantly different between RPL patients and control participants. Therefore, although GP6 polymorphisms may be useful as biomarkers of RPL, additional studies with heterogeneous cohorts are required to better understand the influence of GP6 and assess its performance as a biomarker. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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Review

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30 pages, 2615 KiB

Open AccessReview

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

by Valeria D’Argenio, Lara Dittfeld, Paolo Lazzeri, Rossella Tomaiuolo and Ennio Tasciotti

Genes 2021, 12(4), 605; https://doi.org/10.3390/genes12040605 - 20 Apr 2021

Cited by 7 | Viewed by 4099

Abstract

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. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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12 pages, 1397 KiB

Open AccessReview

Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics

by Thomas Eggermann

Genes 2020, 11(12), 1454; https://doi.org/10.3390/genes11121454 - 03 Dec 2020

Cited by 22 | Viewed by 5100

Abstract

Prenatal detection of uniparental disomy (UPD) is a methodological challenge, and a positive testing result requires comprehensive considerations on the clinical consequences as well as ethical issues. Whereas prenatal testing for UPD in families which are prone to UPD formation (e.g., in case of chromosomal variants, imprinting disorders) is often embedded in genetic counselling, the incidental identification of UPD is often more difficult to manage. With the increasing application of high-resolution test systems enabling the identification of UPD, an increase in pregnancies with incidental detection of UPD can be expected. This paper will cover the current knowledge on uniparental disomies, their clinical consequences with focus on prenatal testing, genetic aspects and predispositions, genetic counselling, as well as methods (conventional tests and high-throughput assays). Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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Other

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12 pages, 863 KiB

Open AccessPerspective

Non-Invasive Prenatal Testing: Current Perspectives and Future Challenges

by Luigi Carbone, Federica Cariati, Laura Sarno, Alessandro Conforti, Francesca Bagnulo, Ida Strina, Lucio Pastore, Giuseppe Maria Maruotti and Carlo Alviggi

Genes 2021, 12(1), 15; https://doi.org/10.3390/genes12010015 - 24 Dec 2020

Cited by 39 | Viewed by 10540

Abstract

Fetal aneuploidies are among the most common causes of miscarriages, perinatal mortality and neurodevelopmental impairment. During the last 70 years, many efforts have been made in order to improve prenatal diagnosis and prenatal screening of these conditions. Recently, the use of cell-free fetal DNA (cff-DNA) testing has been increasingly used in different countries, representing an opportunity for non-invasive prenatal screening of pregnant women. The aim of this narrative review is to describe the state of the art and the main strengths and limitations of this test for prenatal screening of fetal aneuploidies. Full article

(This article belongs to the Special Issue Genetics and Genomics of Reproductive Medicine)

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