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Prenatal Genetic Screening and Diagnosis
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Prenatal Genetic Screening and Diagnosis

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 18437

Special Issue Editors

Prof. Dr. Philip J. Young

E-Mail Website
Guest Editor
Associate Professor, School of Life Sciences, University of Warwick, Coventry, UK
Interests: spinal muscular atrophy; neuromuscular disorders; protein biochemistry; prenatal and newborn genetic screening
Dr. Elizabeth C. Young

E-Mail
Guest Editor
Clinical Scientist, West Midlands Regional Genetics Laboratory, Women’s Hospital, Birmingham, UK
Interests: familial cancers; prenatal diagnostic diagnostics and screening; non-invasive prenatal testing (NIPT); non-invasive prenatal diagnosis (NIPD)
Prof. Dr. Felicity K. Boardman

E-Mail Website
Guest Editor
Associate Professor, Warwick Medical School, University of Warwick, Warwick, UK
Interests: mixed methods; genetic and reproductive technologies; disability; Spinal Muscular Atrophy; qualitative research methods; stigma

Special Issue Information

Dear Colleagues,

Over recent years there has been a paired expansion in both our understanding of the genetic causes of disease and the genetic technologies that can be used to diagnose or test for them. However, in most health services prenatal screening usually still involves a small, limited number of routine tests. For example, in the UK expecting mothers are routinely screened for infectious disease, trisomy-disorders (Edwards’, Down’s and Patau’s syndromes), sickle cell anemia, thalassemia and haemoglobin disorders; while testing for autosomal disorders tends to only occur in mothers with a family history of the conditions. When the current panels are reviewed in the context our expanded capabilities, there is a clear need to review and discuss priorities within the field.

In this special issue of the Journal of Clinical Medicine, on Prenatal Genetic Screening and Diagnosis, we are offering a forum to facilitate these discussions. We are requesting articles covering advances in genetic technologies, epidemiology of genetic disorders (including incidence rate and carrier frequency studies), screening ethics, non-invasive prenatal technologies (NIPT and NIPD), assay performance (sensitivity, specificity, accuracy, PPV and NPV) and economic modeling. We welcome papers on screening and diagnostic assays that have already been approved by the various regulatory bodies, but also those where cases are being prepared.

Prof. Dr. Philip J. Young
Dr Elizabeth C. Young
Prof. Dr. Felicity K. Boardman
Guest Editors

Manuscript Submission Information

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Prenatal diagnostics and screening
  • Next-generation sequencing
  • Exome sequencing
  • Non-invasive prenatal testing
  • Non-invasive prenatal diagnosis
  • Biomarkers

Published Papers (5 papers)

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Research

12 pages, 857 KiB  
Article
Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies
by Amy Gerrish, Benjamin Bowns, Chipo Mashayamombe-Wolfgarten, Elizabeth Young, Samantha Court, Joshua Bott, Maureen McCalla, Simon Ramsden, Michael Parks, David Goudie, Sue Carless, Samuel Clokie, Trevor Cole and Stephanie Allen
J. Clin. Med. 2020, 9(11), 3517; https://doi.org/10.3390/jcm9113517 - 30 Oct 2020
Cited by 11 | Viewed by 2760
Abstract
Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the RB1 gene. Early diagnosis of children at risk of inheriting an RB1 mutation is crucial to achieve optimal clinical [...] Read more.
Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the RB1 gene. Early diagnosis of children at risk of inheriting an RB1 mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks’ gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo RB1 variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication (n = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis)
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11 pages, 671 KiB  
Article
Cell-Free DNA in the Investigation of Miscarriage
by Emily Colley, Adam J. Devall, Helen Williams, Susan Hamilton, Paul Smith, Neil V. Morgan, Siobhan Quenby, Arri Coomarasamy and Stephanie Allen
J. Clin. Med. 2020, 9(11), 3428; https://doi.org/10.3390/jcm9113428 - 26 Oct 2020
Cited by 12 | Viewed by 2871
Abstract
Approximately one in four pregnancies result in pregnancy loss, and ~50% of these miscarriages are caused by chromosomal abnormalities. Genetic investigations are recommended after three consecutive miscarriages on products of conception (POC) tissue. Cell-free DNA (cfDNA) has been utilised for prenatal screening, but [...] Read more.
Approximately one in four pregnancies result in pregnancy loss, and ~50% of these miscarriages are caused by chromosomal abnormalities. Genetic investigations are recommended after three consecutive miscarriages on products of conception (POC) tissue. Cell-free DNA (cfDNA) has been utilised for prenatal screening, but very little work has been carried out in nonviable pregnancies. We investigated the use of cfDNA from maternal blood to identify chromosomal abnormalities in miscarriage. One hundred and two blood samples from women experiencing a first trimester miscarriage were collected and stored. The mean gestational age was 7.1 weeks (range: 5–11 weeks). In this research, samples without a genetic test result from POC were not analysed. CfDNA was extracted and analysed using a modified commercial genome-wide non-invasive prenatal test. No results were provided to the patient. In 57 samples, cytogenetic results from POC analysis were available. Chromosomal abnormalities were identified in 47% (27/57) of POC analyses, and cfDNA analysis correctly identified 59% (16/27) of these. In total, 75% (43/57) of results were correctly identified. The average cfDNA fetal fraction was 6% (2–19%). In conclusion, cfDNA can be used to detect chromosomal abnormalities in miscarriages where the ‘fetal fraction’ is high enough; however, more studies are required to identify variables that can affect the overall results. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis)
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13 pages, 905 KiB  
Article
Strategy for Use of Genome-Wide Non-Invasive Prenatal Testing for Rare Autosomal Aneuploidies and Unbalanced Structural Chromosomal Anomalies
by Pascale Kleinfinger, Laurence Lohmann, Armelle Luscan, Detlef Trost, Laurent Bidat, Véronique Debarge, Vanina Castaigne, Marie-Victoire Senat, Marie-Pierre Brechard, Lucie Guilbaud, Gwenaël Le Guyader, Véronique Satre, Hélène Laurichesse Delmas, Hakima Lallaoui, Marie-Christine Manca-Pellissier, Aicha Boughalem, Mylene Valduga, Farah Hodeib, Alexandra Benachi and Jean Marc Costa
J. Clin. Med. 2020, 9(8), 2466; https://doi.org/10.3390/jcm9082466 - 1 Aug 2020
Cited by 16 | Viewed by 4396
Abstract
Atypical fetal chromosomal anomalies are more frequent than previously recognized and can affect fetal development. We propose a screening strategy for a genome-wide non-invasive prenatal test (NIPT) to detect these atypical chromosomal anomalies (ACAs). Two sample cohorts were tested. Assay performances were determined [...] Read more.
Atypical fetal chromosomal anomalies are more frequent than previously recognized and can affect fetal development. We propose a screening strategy for a genome-wide non-invasive prenatal test (NIPT) to detect these atypical chromosomal anomalies (ACAs). Two sample cohorts were tested. Assay performances were determined using Cohort A, which consisted of 192 biobanked plasma samples—42 with ACAs, and 150 without. The rate of additional invasive diagnostic procedures was determined using Cohort B, which consisted of 3097 pregnant women referred for routine NIPT. Of the 192 samples in Cohort A, there were four initial test failures and six discordant calls; overall sensitivity was 88.1% (37/42; CI 75.00–94.81) and specificity was 99.3% (145/146; CI 96.22–99.88). In Cohort B, there were 90 first-pass failures (2.9%). The rate of positive results indicating an anomaly was 1.2% (36/3007) and 0.57% (17/3007) when limited to significant unbalanced chromosomal anomalies and trisomies 8, 9, 12, 14, 15, 16, and 22. These results show that genome-wide NIPT can screen for ACAs with an acceptable sensitivity and a small increase in invasive testing, particularly for women with increased risk following maternal serum screening and by limiting screening to structural anomalies and the most clinically meaningful trisomies. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis)
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11 pages, 1665 KiB  
Article
Clinical Outcomes of Single Mosaic Embryo Transfer: High-Level or Low-Level Mosaic Embryo, Does It Matter?
by Pin-Yao Lin, Chun-I Lee, En-Hui Cheng, Chun-Chia Huang, Tsung-Hsien Lee, Hui-Hsin Shih, Yi-Ping Pai, Yi-Chun Chen and Maw-Sheng Lee
J. Clin. Med. 2020, 9(6), 1695; https://doi.org/10.3390/jcm9061695 - 2 Jun 2020
Cited by 39 | Viewed by 5282
Abstract
Recently, reports showed that embryos identified as mosaic after preimplantation genetic testing for aneuploid (PGT-A) could result in live birth with lower pregnancy and higher pregnancy loss rates compared with euploid embryos. However, the effects of mosaicism level on reproductive outcomes remain controversial. [...] Read more.
Recently, reports showed that embryos identified as mosaic after preimplantation genetic testing for aneuploid (PGT-A) could result in live birth with lower pregnancy and higher pregnancy loss rates compared with euploid embryos. However, the effects of mosaicism level on reproductive outcomes remain controversial. This study aimed to examine the level of mosaicism on pregnancy outcomes. Single mosaic embryo transfer was offered to 108 women who only had mosaic embryos. Mosaic embryos were labeled by utilizing next generation sequencing (NGS) based PGT-A for day 5/6 trophectoderm (TE) biopsies. TE biopsies containing < 50% abnormal cells were classified as low-level mosaicism and ≥ 50% as high-level mosaicism. To further confirm the concordance of chromosome constitution between TE and inner cell mass (ICM), 41 remaining embryos designated as mosaic blastocysts donated for research were also analyzed. Comparable live birth rate (LBR) but higher miscarriage rate (MR) was found in the high-level group. (LBR: low vs. high: 44.5% vs. 36%; p = 0.45, MR: low vs. high: 5.1% vs. 30.7%; p = 0.012). Analyses of TE and ICM from the remaining mosaic blastocysts show a poor concordance. This preliminary study demonstrated that high-level mosaic embryos could result in comparable LBR but higher MR. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis)
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10 pages, 564 KiB  
Article
Effect of Interval between Human Chorionic Gonadotropin Priming and Ovum Pick-up on the Euploid Probabilities of Blastocyst
by Chun-I Lee, Hsiu-Hui Chen, Chun-Chia Huang, Chien-Hong Chen, En-Hui Cheng, Jing Yang Huang, Maw-Sheng Lee and Tsung-Hsien Lee
J. Clin. Med. 2020, 9(6), 1685; https://doi.org/10.3390/jcm9061685 - 2 Jun 2020
Cited by 4 | Viewed by 2449
Abstract
This retrospective study attempts to elucidate the relevance of the interval between human chorionic gonadotropin priming and oocyte pick-up (hCG-OPU) to the euploidy probability of biopsied blastocysts in preimplantation genetic tests for aneuploidy (PGT-A) cycles. A total of 1889 blastocysts from 511 patients [...] Read more.
This retrospective study attempts to elucidate the relevance of the interval between human chorionic gonadotropin priming and oocyte pick-up (hCG-OPU) to the euploidy probability of biopsied blastocysts in preimplantation genetic tests for aneuploidy (PGT-A) cycles. A total of 1889 blastocysts from 511 patients undergoing PGT- A cycles were used. An analysis of generalized estimating equations (GEE) was used to identify whether the hCG–OPU interval is associated with euploidy probabilities of blastocysts. Accordingly, maternal age (OR: 0.925, 95% CI: 0.903–0.948, p < 0.001) and the hCG–OPU interval (OR: 1.138, 95% CI: 1.028–1.260, p = 0.013) were the two significant factors associated with the euploidy probabilities. The Cochran-Armitage trend test demonstrated that the blastocyst euploidy percentage increased progressively with the increasing hCG-OPU interval in normal responders (p = 0.006) and advanced maternal age (age ≥38 years; p = 0.020) groups. In normal responders, the euploidy rate was highest in the 38–39 h interval (43.1%, 47/109). In contrast, the euploidy rate was lowest in the 34–35 h interval (28.7%, 29/105). In conclusion, the present study demonstrated that at an hCG-OPU interval between 34–39 h, the longer the hCG-OPU interval, the higher the probability of euploidy for blastocysts. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis)
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