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Prenatal Genetic Screening and Diagnosis-Part 2
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Prenatal Genetic Screening and Diagnosis-Part 2

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 (20 February 2014) | Viewed by 220749

Special Issue Editors

Prof. Dr. Peter Benn

E-Mail Website
Guest Editor
Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, L1049, Farmington, CT 06030-3808, USA
Interests: prenatal screening and diagnosis; non-invasive prenatal testing; cytogenetics; microarray; pregnancy biomarkers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Eugene Pergament

E-Mail Website
Guest Editor
Northwestern Reproductive Genetics, ReproGenetics Research and Department of Obstetrics and Gynecology, School of Medicine, Northwestern University, 680 North Lake Shore Drive, Suite 1230, Chicago, IL 60611, USA
Interests: prenatal screening and diagnosis; genetic counseling; carrier screening; non-invasive prenatal screening
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For the past five decades, there has been an increasing pace of progress in screening and diagnosis of genetic disorders in the fetus. Biochemical tests on maternal serum and ultrasound identification of fetal abnormalities and biomarkers currently provide the basis for identifying high-risk pregnancies. The ability to analyze cell-free DNA in maternal plasma now provides the opportunity to further test for fetal aneuploidy and some single gene disorders. Definitive diagnosis still requires invasive sampling methods (amniocentesis and chorionic villus sampling) but this testing has been substantially enhanced through the addition of chromosome and single nucleotide polymorphism (SNP) microarrays so that now small copy number changes (microdeltions/microduplications) can be reliably detected. Pre-implementation genetic testing has also benefited from the application of advances in molecular genetics with an expanded number of mutations and imbalances identifiable in embryos. In the near future, it is expected that DNA sequencing will provide unprecedented levels of information about the fetal genome in regard to form (physical structure) and function (behavior). How these technical advances will be introduced into obstetric care raises significant ethical, legal and moral challenges and clinical services will likely vary considerably in different healthcare settings.

This Special Issue compiles articles that reflect the current state-of-the-art and are also indicative of some of the anticipated advances in prenatal screening and diagnosis.

Prof. Dr. Peter Benn
Prof. Dr. Eugene Pergament
Guest Editors

Manuscript Submission Information

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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
  • maternal serum
  • ultrasound
  • non-invasive testing
  • microarray
  • aneuploidy
  • genetic disorders
  • pre-implantation

Published Papers (26 papers)

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Editorial

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225 KiB  
Editorial
The Role of RNAs and microRNAs in Non-Invasive Prenatal Diagnosis
by Antonio Farina
J. Clin. Med. 2014, 3(2), 440-452; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020440 - 06 May 2014
Cited by 8 | Viewed by 5303
Abstract
In this paper, all possible clinical applications of circulating mRNA and miRNA for non-invasive prenatal diagnosis appearing in the medical literature so far are described. Data from the literature have also been reported and commented on along with some possible future applications. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)

Research

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1119 KiB  
Article
Non-Invasive Prenatal Diagnosis in the Management of Preimplantation Genetic Diagnosis Pregnancies
by Ana Bustamante-Aragones, Sara Perlado-Marina, Maria José Trujillo-Tiebas, Jesús Gallego-Merlo, Isabel Lorda-Sanchez, Luz Rodríguez-Ramirez, Concepcion Linares, Corazón Hernandez and Marta Rodriguez De Alba
J. Clin. Med. 2014, 3(3), 913-922; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030913 - 14 Aug 2014
Cited by 8 | Viewed by 6741
Abstract
Prenatal diagnosis (PD) is recommended in pregnancies after a Preimplantation Genetic Diagnosis (PGD). However, conventional PD entails a risk of fetal loss which makes PGD patients reluctant to undergo obstetric invasive procedures. The presence of circulating fetal DNA in maternal blood allows performing [...] Read more.
Prenatal diagnosis (PD) is recommended in pregnancies after a Preimplantation Genetic Diagnosis (PGD). However, conventional PD entails a risk of fetal loss which makes PGD patients reluctant to undergo obstetric invasive procedures. The presence of circulating fetal DNA in maternal blood allows performing a non-invasive prenatal diagnosis (NIPD) without risk for the pregnancy outcome. This work shows the introduction of NIPD for confirmation of PGD results in eight pregnancies. In those pregnancies referred to PGD for an X-linked disorder (six out of eight), fetal sex determination in maternal blood was performed to confirm fetal sex. One pregnancy referred to PGD for Marfan syndrome and one referred for Huntington disease (HD) were also analyzed. In seven out of eight cases, PGD results were confirmed by NIPD in maternal blood. No results were obtained in the HD pregnancy. NIPD in PGD pregnancies can be a reliable alternative for couples that after a long process feel reluctant to undergo PD due to the risk of pregnancy loss. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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825 KiB  
Article
Impact of Cell-Free Fetal DNA Screening on Patients’ Choice of Invasive Procedures after a Positive California Prenatal Screen Result
by Forum T. Shah, Kathryn Steinhaus French, Kathryn E. Osann, Maureen Bocian, Marilyn C. Jones and Lauren Korty
J. Clin. Med. 2014, 3(3), 849-864; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030849 - 24 Jul 2014
Cited by 3 | Viewed by 7890
Abstract
Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively). Women with positive California Prenatal [...] Read more.
Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively). Women with positive California Prenatal Screening Program (CPSP) results have the option of diagnostic testing to determine definitively if the fetus has a chromosomal abnormality. Cell-free fetal (cff-) DNA screening for Trisomies 13, 18, and 21 was first offered in 2012, allowing women with positive screens to choose additional screening before diagnostic testing. Cff-DNA sensitivity rates are as high as 99.9% and 99.1%, with false positive rates of 0.4% and 0.1%, for Trisomies 18 and 21, respectively. A retrospective chart review was performed in 2012 on 500 CPSP referrals at the University of California, San Diego Thornton Hospital. Data were collected prior to and after the introduction of cff-DNA. There was a significant increase in the number of participants who chose to pursue additional testing and a decrease in the number of invasive procedures performed after cff-DNA screening was available. We conclude that as fetal aneuploidy screening improves, the number of invasive procedures will continue to decrease. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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784 KiB  
Article
A 26-Year Experience in Chorionic Villus Sampling Prenatal Genetic Diagnosis
by Paula Jorge, Maria Manuela Mota-Freitas, Rosário Santos, Maria Luz Silva, Gabriela Soares and Ana Maria Fortuna
J. Clin. Med. 2014, 3(3), 838-848; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030838 - 24 Jul 2014
Cited by 2 | Viewed by 7304
Abstract
This report describes the trends of chorionic villus sampling (CVS) referred for prenatal genetic diagnosis in the past two and a half decades in a Portuguese Center. Our cohort of 491 CVS was mostly performed by the transcervical method at the 12th gestational [...] Read more.
This report describes the trends of chorionic villus sampling (CVS) referred for prenatal genetic diagnosis in the past two and a half decades in a Portuguese Center. Our cohort of 491 CVS was mostly performed by the transcervical method at the 12th gestational week. Data collected within the framework of this study relate to the following: sampling method, referral reason versus abnormality and incidence of procedure-related pregnancy loss, that declined to about 0.5% over the last 15 years. The year 2000 represented a change in referral reasons for chorionic tissue collection, shifting from almost exclusively for cytogenetic testing to an increasing number of molecular tests for monogenic disorders. Herein, success rates as well as cytogenetic and/or molecular DNA results are presented. These latter include not only tests for several monogenic disorders, but also aneuploidy and maternal cell contamination screening. This retrospective analysis reiterates that CVS is a safe and reliable first trimester technique for prenatal diagnosis in high genetic risk pregnancies. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Communication
Pregnancy Loss Following Amniocentesis or CVS Sampling—Time for a Reassessment of Risk
by Caroline Ogilvie and Ranjit Akolekar
J. Clin. Med. 2014, 3(3), 741-746; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030741 - 08 Jul 2014
Cited by 7 | Viewed by 7300
Abstract
Risk of procedure-related pregnancy loss is currently widely quoted in the UK as 1% for amniocentesis and 1.5% for chorionic villus sampling. Published data suggest that these risk figures are out of date and inaccurate, and that new guidelines are required for pre-test [...] Read more.
Risk of procedure-related pregnancy loss is currently widely quoted in the UK as 1% for amniocentesis and 1.5% for chorionic villus sampling. Published data suggest that these risk figures are out of date and inaccurate, and that new guidelines are required for pre-test counseling. It is our opinion that accurate and evidence-based information concerning miscarriage risk is vital when counseling women, as exaggeration of this risk may deter women from testing, or cause unjustified remorse if a miscarriage ensues. It is also essential that health-care economists are aware of the up-to-date evidence on “procedure-related risk” when applying risk-benefit analysis to assess new technology for non-invasive screening. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Article
Knowledge and Educational Needs about Pre-Implantation Genetic Diagnosis (PGD) among Oncology Nurses
by Gwendolyn P. Quinn, Caprice Knapp, Ivana Sehovic, Danielle Ung, Meghan Bowman, Luis Gonzalez and Susan T. Vadaparampil
J. Clin. Med. 2014, 3(2), 632-645; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020632 - 20 Jun 2014
Cited by 7 | Viewed by 8241
Abstract
Preimplantation genetic diagnosis (PGD), a form of assisted reproductive technology, is a new technology with limited awareness among health care professionals and hereditary cancer families. Nurses play a key role in the care of patients and are often in an ideal position to [...] Read more.
Preimplantation genetic diagnosis (PGD), a form of assisted reproductive technology, is a new technology with limited awareness among health care professionals and hereditary cancer families. Nurses play a key role in the care of patients and are often in an ideal position to discuss and refer patients on sensitive quality of life issues, such as PGD. Two hundred and one nurses at Moffitt Cancer Center (MCC) responded to an online survey assessing knowledge and educational needs regarding PGD and families with hereditary cancer. The majority of respondents were female (n = 188), white (n = 175), had an RN/BSN degree (n = 83), and provided outpatient care at the cancer center (n = 102). More than half of respondents (78%) were unfamiliar with PGD prior to the survey and respondents who had heard of PGD had limited knowledge. More than half of the participants reported PGD was an acceptable option for families with hereditary cancer syndromes and thought individuals with a strong family or personal history should be provided with information about PGD. This study indicates that oncology nurses may benefit from and desire education about PGD. With advances in reproductive technology and options, further PGD education is needed among healthcare professionals. An examination of current oncology nursing curriculum and competencies regarding genetic education may identify need for future revisions and updates. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Article
It’s More Than a Blood Test: Patients’ Perspectives on Noninvasive Prenatal Testing
by Ruth M. Farrell, Mary Beth Mercer, Patricia K. Agatisa, Marissa B. Smith and Elliot Philipson
J. Clin. Med. 2014, 3(2), 614-631; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020614 - 19 Jun 2014
Cited by 34 | Viewed by 7600
Abstract
Noninvasive prenatal testing (NIPT) offers pregnant women a new risk assessment tool for fetal aneuploidy that is superior to conventional screening tests. We conducted focus groups with women who were currently pregnant or had recently delivered in the past year to characterize their [...] Read more.
Noninvasive prenatal testing (NIPT) offers pregnant women a new risk assessment tool for fetal aneuploidy that is superior to conventional screening tests. We conducted focus groups with women who were currently pregnant or had recently delivered in the past year to characterize their perspectives about NIPT and to explore factors they would consider during decision making about its use. Women identified accuracy, early timing, testing ease, and determination of fetal sex as advantages of NIPT over other screens, and the noninvasive method of NIPT as an advantage over diagnostic tests. False positive and false negative results, anxiety, cost and insurance coverage were seen as disadvantages of NIPT. Women who do not want fetal aneuploidy information most likely will not undergo NIPT, despite its advantages over other screening tests. However, given its advantages, the decision to have NIPT is straightforward for women who want genetic information about the fetus. Women emphasized the need to make autonomous, private, and informed choices about NIPT, as they would with any prenatal genetic testing option. These perspectives may guide clinicians to conduct effective and clinically relevant counseling with pregnant women who consider utilizing this new genetic technology. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
536 KiB  
Article
First Trimester Aneuploidy Screening Markers in Women with Pre-Gestational Diabetes Mellitus
by Padmalatha Gurram, Peter Benn, James Grady, Anne-Marie Prabulos and Winston Campbell
J. Clin. Med. 2014, 3(2), 480-490; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020480 - 08 May 2014
Cited by 4 | Viewed by 6624
Abstract
Objective: To investigate whether maternal serum pregnancy associated plasma protein-A (PAPP-A), total β human chorionic gonadotropin (hCG) levels and nuchal translucency (NT) measurements differ in women with pre-gestational diabetes mellitus (PGDM) compared to non-diabetic controls and to assess whether correction factors are needed [...] Read more.
Objective: To investigate whether maternal serum pregnancy associated plasma protein-A (PAPP-A), total β human chorionic gonadotropin (hCG) levels and nuchal translucency (NT) measurements differ in women with pre-gestational diabetes mellitus (PGDM) compared to non-diabetic controls and to assess whether correction factors are needed for diabetic women in calculation of aneuploidy risks. Study Design: We performed a retrospective study of all women who underwent first trimester aneuploidy screening (11 + 0 to 13 + 6 weeks) from 2005 to 2011. The primary study outcome was the difference in PAPP-A, β-hCG and NT multiples of median between women with PGDM and non-diabetic women. Results: Of 6741 eligible patients, 103 patients with PGDM were using insulin and 4 patients were using oral hypoglycemic agents; the latter were excluded due to small number. There was 12% reduction of median PAPP-A (p = 0.001) and 18% reduction of median hCG (p = 0.006) in women with PGDM receiving insulin. There was no difference in NT. Conclusions: In women with PGDM receiving insulin, PAPP-A and β-hCG levels are significantly lower compared to non-diabetic women. This suggests that when calculating risks for aneuploidy, correction factors should be considered to adjust PAPP-A and β-hCG concentrations to those seen in non-diabetic women. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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163 KiB  
Article
Prenatal Isolated Ventricular Septal Defect May Not Be Associated with Trisomy 21
by Ori Shen, Sari Lieberman, Benjamin Farber, Daniel Terner, Amnon Lahad and Ephrat Levy-Lahad
J. Clin. Med. 2014, 3(2), 432-439; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020432 - 23 Apr 2014
Cited by 8 | Viewed by 6568
Abstract
The aim of this study was to examine if isolated fetal ventricular septal defect (VSD) is associated with trisomy 21. One hundred twenty six cases with prenatal VSD diagnosed by a pediatric cardiologist were reviewed. Cases with known risk factors for congenital heart [...] Read more.
The aim of this study was to examine if isolated fetal ventricular septal defect (VSD) is associated with trisomy 21. One hundred twenty six cases with prenatal VSD diagnosed by a pediatric cardiologist were reviewed. Cases with known risk factors for congenital heart disease, the presence of other major anomalies, soft signs for trisomy 21 or a positive screen test for trisomy 21 were excluded. Ninety two cases formed the study group. None of the cases in the study group had trisomy 21. The upper limit of prevalence for trisomy 21 in isolated VSD is 3%. When prenatal VSD is not associated with other major anomalies, soft markers for trisomy 21 or a positive nuchal translucency or biochemical screen, a decision whether to perform genetic amniocentesis should be individualized. The currently unknown association between isolated VSD and microdeletions and microduplications should be considered when discussing this option. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
201 KiB  
Article
Can Characteristics of Reciprocal Translocations Predict the Chance of Transferable Embryos in PGD Cycles?
by Elsbeth Dul, Jannie Van Echten-Arends, Henk Groen, Peter Kastrop, Lucie Amory-van Wissen, John Engelen, Jolande Land, Edith Coonen and Conny Van Ravenswaaij-Arts
J. Clin. Med. 2014, 3(2), 348-358; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020348 - 02 Apr 2014
Cited by 4 | Viewed by 6368
Abstract
Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common [...] Read more.
Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common experience is that reciprocal translocation carriers produce a high percentage of unbalanced embryos, which cannot be transferred. Therefore, the pregnancy rates in PGD in this patient group are low. In a cohort of 85 reciprocal translocation carriers undergoing PGD we have searched for cytogenetic characteristics of the translocations that can predict the percentage of balanced embryos. Using shape algorithms, the most likely segregation mode per translocation was determined. Shape algorithm, breakpoint location, and relative chromosome segment sizes proved not to be independent predictors of the percentage of balanced embryos. The ratio of the relative sizes of the translocated segments of both translocation chromosomes can give some insight into the chance of transferable embryos: Very asymmetrical translocations have a higher risk of unbalanced products (p = 0.048). Counseling of the couples on the pros and cons of all their reproductive options remains very important. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
217 KiB  
Article
Preferences for Prenatal Tests for Cystic Fibrosis: A Discrete Choice Experiment to Compare the Views of Adult Patients, Carriers of Cystic Fibrosis and Health Professionals
by Melissa Hill, Ranjan Suri, Edward F. Nash, Stephen Morris and Lyn S. Chitty
J. Clin. Med. 2014, 3(1), 176-190; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3010176 - 14 Feb 2014
Cited by 14 | Viewed by 8630
Abstract
As new technologies enable the development of non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF), research examining stakeholder views is essential for the preparation of implementation strategies. Here, we compare the views of potential service users with those of health professionals who provide [...] Read more.
As new technologies enable the development of non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF), research examining stakeholder views is essential for the preparation of implementation strategies. Here, we compare the views of potential service users with those of health professionals who provide counselling for prenatal tests. A questionnaire incorporating a discrete choice experiment examined preferences for key attributes of NIPD and explored views on NIPD for CF. Adult patients (n = 92) and carriers of CF (n = 50) were recruited from one children’s and one adult NHS specialist CF centre. Health professionals (n = 70) were recruited via an e-mail invitation to relevant professional bodies. The key attribute affecting service user testing preferences was no miscarriage risk, while for health professionals, accuracy and early testing were important. The uptake of NIPD by service users was predicted to be high and includes couples that would currently decline invasive testing. Many service users (47%) and health professionals (55.2%) thought the availability of NIPD for CF would increase the pressure to undergo prenatal testing. Most service users (68.5%) thought NIPD for CF should be offered to all pregnant women, whereas more health professionals (68.2%) thought NIPD should be reserved for known carrier couples. The implications for clinical practice are discussed. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Article
Maternal Germinal Trisomy 21 in Down Syndrome
by Maj A. Hultén, Linn Öijerstedt, Erik Iwarsson and Jon Jonasson
J. Clin. Med. 2014, 3(1), 167-175; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3010167 - 28 Jan 2014
Cited by 8 | Viewed by 8223
Abstract
It has now been over 50 years since it was discovered that Down syndrome is caused by an extra chromosome 21, i.e., trisomy 21. In the interim, it has become clear that in the majority of cases, the extra chromosome is inherited [...] Read more.
It has now been over 50 years since it was discovered that Down syndrome is caused by an extra chromosome 21, i.e., trisomy 21. In the interim, it has become clear that in the majority of cases, the extra chromosome is inherited from the mother, and there is, in this respect, a strong maternal age effect. Numerous investigations have been devoted to clarifying the underlying mechanism, most recently suggesting that this situation is exceedingly complex, involving both biological and environmental factors. On the other hand, it has also been proposed that germinal trisomy 21 mosaicism, arising during the very early stages of maternal oogenesis with accumulation of trisomy 21 germ cells during subsequent development, may be the main predisposing factor. We present data here on the incidence of trisomy 21 mosaicism in a cohort of normal fetal ovarian samples, indicating that an accumulation of trisomy 21 germ cells does indeed take place during fetal oogenesis, i.e., from the first to the second trimester of pregnancy. We presume that this accumulation of trisomy 21 (T21) cells is caused by their delay in maturation and lagging behind the normal cells. We further presume that this trend continues during the third trimester of pregnancy and postnatally, up until ovulation, thereby explaining the maternal age effect in Down syndrome. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review

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667 KiB  
Review
Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis
by Lauren Westerfield, Sandra Darilek and Ignatia B. Van den Veyver
J. Clin. Med. 2014, 3(3), 1018-1032; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3031018 - 12 Sep 2014
Cited by 68 | Viewed by 7881
Abstract
Prenatal genetic screening and testing provides prospective parents information about the health of their fetus. It is offered to find or address an increased risk for chromosomal abnormalities or other genetic conditions in the fetus or to identify the cause of fetal structural [...] Read more.
Prenatal genetic screening and testing provides prospective parents information about the health of their fetus. It is offered to find or address an increased risk for chromosomal abnormalities or other genetic conditions in the fetus or to identify the cause of fetal structural abnormalities detected by prenatal imaging. Genome-wide tests, such as the already widely-used chromosomal microarray analysis and emerging diagnostic whole exome and whole genome sequencing, have improved the ability to detect clinically significant findings, but have also increased the chance of detecting incidental findings and variants of uncertain significance. There is an extensive ongoing discussion about optimal strategies for diagnostic laboratories to report such findings and for providers to communicate them with patients. While consensus opinions and guidelines are beginning to appear, they often exclude the prenatal setting, due to its unique set of challenging considerations. These include more limited knowledge of the impact of genetic variants when prospectively detected in an ongoing pregnancy, the absence or limitations of detecting clinically recognizable phenotypes at the time of testing and the different decision-making processes that will ensue from testing. In this review, we examine these challenges within the medical ethical framework unique to prenatal care. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Screening and Invasive Testing in Twins
by Giovanni Monni, Ambra Iuculano and Maria Angelica Zoppi
J. Clin. Med. 2014, 3(3), 865-882; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030865 - 29 Jul 2014
Cited by 4 | Viewed by 6024
Abstract
Prenatal screening and testing for trisomy 21 in twin pregnancies poses a number of challenges: the exact estimate of the a priori risk of trisomy 21, the choice of prenatal screening test and/or invasive techniques to employ for the diagnosis and the impact [...] Read more.
Prenatal screening and testing for trisomy 21 in twin pregnancies poses a number of challenges: the exact estimate of the a priori risk of trisomy 21, the choice of prenatal screening test and/or invasive techniques to employ for the diagnosis and the impact of the result on the options of treatment in case of discordant results within a twin pair or among multiples. These different aspects are discussed below while recognizing that many issues remain unresolved. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Chromosomal Mosaicism in Human Feto-Placental Development: Implications for Prenatal Diagnosis
by Francesca Romana Grati
J. Clin. Med. 2014, 3(3), 809-837; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030809 - 24 Jul 2014
Cited by 75 | Viewed by 21336
Abstract
Chromosomal mosaicism is one of the primary interpretative issues in prenatal diagnosis. In this review, the mechanisms underlying feto-placental chromosomal mosaicism are presented. Based on the substantial retrospective diagnostic experience with chorionic villi samples (CVS) of a prenatal diagnosis laboratory the following items [...] Read more.
Chromosomal mosaicism is one of the primary interpretative issues in prenatal diagnosis. In this review, the mechanisms underlying feto-placental chromosomal mosaicism are presented. Based on the substantial retrospective diagnostic experience with chorionic villi samples (CVS) of a prenatal diagnosis laboratory the following items are discussed: (i) The frequency of the different types of mosaicism (confined placental, CPM, and true fetal mosaicisms, TFM); (ii) The risk of fetal confirmation after the detection of a mosaic in CVS stratified by chromosome abnormality and placental tissue involvement; (iii) The frequency of uniparental disomy for imprinted chromosomes associated with CPM; (iv) The incidence of false-positive and false-negative results in CVS samples analyzed by only (semi-)direct preparation or long term culture; and (v) The implications of the presence of a feto-placental mosaicism for microarray analysis of CVS and non-invasive prenatal screening (NIPS). Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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202 KiB  
Review
Limitations of Aneuploidy and Anomaly Detection in the Obese Patient
by Paula Zozzaro-Smith, Lisa M. Gray, Stephen J. Bacak and Loralei L. Thornburg
J. Clin. Med. 2014, 3(3), 795-808; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030795 - 17 Jul 2014
Cited by 12 | Viewed by 6038
Abstract
Obesity is a worldwide epidemic and can have a profound effect on pregnancy risks. Obese patients tend to be older and are at increased risk for structural fetal anomalies and aneuploidy, making screening options critically important for these women. Failure rates for first-trimester [...] Read more.
Obesity is a worldwide epidemic and can have a profound effect on pregnancy risks. Obese patients tend to be older and are at increased risk for structural fetal anomalies and aneuploidy, making screening options critically important for these women. Failure rates for first-trimester nuchal translucency (NT) screening increase with obesity, while the ability to detect soft-markers declines, limiting ultrasound-based screening options. Obesity also decreases the chances of completing the anatomy survey and increases the residual risk of undetected anomalies. Additionally, non-invasive prenatal testing (NIPT) is less likely to provide an informative result in obese patients. Understanding the limitations and diagnostic accuracy of aneuploidy and anomaly screening in obese patients can help guide clinicians in counseling patients on the screening options. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Exome Sequencing in Fetuses with Structural Malformations
by Fiona L. Mackie, Keren J. Carss, Sarah C. Hillman, Matthew E. Hurles and Mark D. Kilby
J. Clin. Med. 2014, 3(3), 747-762; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030747 - 08 Jul 2014
Cited by 15 | Viewed by 7682
Abstract
Prenatal diagnostic testing is a rapidly advancing field. An accurate diagnosis of structural anomalies and additional abnormalities in fetuses with structural anomalies is important to allow “triage” and designation of prognosis. This will allow parents to make an informed decision relating to the [...] Read more.
Prenatal diagnostic testing is a rapidly advancing field. An accurate diagnosis of structural anomalies and additional abnormalities in fetuses with structural anomalies is important to allow “triage” and designation of prognosis. This will allow parents to make an informed decision relating to the pregnancy. This review outlines the current tests used in prenatal diagnosis, focusing particularly on “new technologies” such as exome sequencing. We demonstrate the utility of exome sequencing above that of conventional karyotyping and Chromosomal Microarray (CMA) alone by outlining a recent proof of concept study investigating 30 parent-fetus trios where the fetus is known to have a structural anomaly. This may allow the identification of pathological gene anomalies and consequently improved prognostic profiling, as well as excluding anomalies and distinguishing between de novo and inherited mutations, in order to estimate the recurrence risk in future pregnancies. The potential ethical dilemmas surrounding exome sequencing are also considered, and the future of prenatal genetic diagnosis is discussed. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
The Psychological Challenges of Replacing Conventional Karyotyping with Genomic SNP Array Analysis in Prenatal Testing
by Sam Riedijk, Karin E. M. Diderich, Sanne L. Van der Steen, Lutgarde C. P. Govaerts, Marieke Joosten, Maarten F. C. M. Knapen, Femke A. T. De Vries, Diane Van Opstal, Aad Tibben and Robert-Jan H. Galjaard
J. Clin. Med. 2014, 3(3), 713-723; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030713 - 03 Jul 2014
Cited by 16 | Viewed by 6066
Abstract
Pregnant couples tend to prefer a maximum of information about the health of their fetus. Therefore, we implemented whole genome microarray instead of conventional karyotyping (CK) for all indications for prenatal diagnosis (PND). The array detects more clinically relevant anomalies, including early onset [...] Read more.
Pregnant couples tend to prefer a maximum of information about the health of their fetus. Therefore, we implemented whole genome microarray instead of conventional karyotyping (CK) for all indications for prenatal diagnosis (PND). The array detects more clinically relevant anomalies, including early onset disorders, not related to the indication and more genetic anomalies of yet unquantifiable risk, so-called susceptibility loci (SL) for mainly neurodevelopmental disorders. This manuscript highlights the psychological challenges in prenatal genetic counselling when using the array and provides counselling suggestions. First, we suggest that pre-test decision counselling should emphasize deliberation about what pregnant couples wish to learn about the future health of their fetus more than information about possible outcomes. Second, pregnant couples need support in dealing with SL. Therefore, in order to consider the SL in a proportionate perspective, the presence of phenotypes associated with SL in the family, the incidence of a particular SL in control populations and in postnatally ascertained patients needs highlighting during post-test genetic counselling. Finally, the decision that couples need to make about the course of their pregnancy is more complicated when the expected phenotype is variable and not quantifiable. Therefore, during post-test psychological counseling, couples should concretize the options of continuing and ending their pregnancy; all underlying feelings and thoughts should be made explicit, as well as the couple’s resources, in order to attain adequate decision-making. As such, pre- and post-test counselling aids pregnant couples in handling the uncertainties that may accompany offering a broader scope of genetic PND using the array. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Maternal Serum Screening Markers and Adverse Outcome: A New Perspective
by David Krantz, Terrence Hallahan, David Janik and Jonathan Carmichael
J. Clin. Med. 2014, 3(3), 693-712; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030693 - 03 Jul 2014
Cited by 10 | Viewed by 8087
Abstract
There have been a number of studies evaluating the association of aneuploidy serum markers with adverse pregnancy outcome. More recently, the development of potential treatments for these adverse outcomes as well as the introduction of cell-free fetal DNA (cffDNA) screening for aneuploidy necessitates [...] Read more.
There have been a number of studies evaluating the association of aneuploidy serum markers with adverse pregnancy outcome. More recently, the development of potential treatments for these adverse outcomes as well as the introduction of cell-free fetal DNA (cffDNA) screening for aneuploidy necessitates a re-evaluation of the benefit of serum markers in the identification of adverse outcomes. Analysis of the literature indicates that the serum markers tend to perform better in identifying pregnancies at risk for the more severe but less frequent form of individual pregnancy complications rather than the more frequent but milder forms of the condition. As a result, studies which evaluate the association of biomarkers with a broad definition of a given condition may underestimate the ability of such markers to identify pregnancies that are destined to develop the more severe form of the condition. Consideration of general population screening using cffDNA solely must be weighed against the fact that traditional screening using serum markers enables detection of severe pregnancy complications, not detectable with cffDNA, of which many may be amenable to treatment options. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Microarray Technology for the Diagnosis of Fetal Chromosomal Aberrations: Which Platform Should We Use?
by Evangelia Karampetsou, Deborah Morrogh and Lyn Chitty
J. Clin. Med. 2014, 3(2), 663-678; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020663 - 20 Jun 2014
Cited by 11 | Viewed by 18089
Abstract
The advantage of microarray (array) over conventional karyotype for the diagnosis of fetal pathogenic chromosomal anomalies has prompted the use of microarrays in prenatal diagnostics. In this review we compare the performance of different array platforms (BAC, oligonucleotide CGH, SNP) and designs (targeted, [...] Read more.
The advantage of microarray (array) over conventional karyotype for the diagnosis of fetal pathogenic chromosomal anomalies has prompted the use of microarrays in prenatal diagnostics. In this review we compare the performance of different array platforms (BAC, oligonucleotide CGH, SNP) and designs (targeted, whole genome, whole genome, and targeted, custom) and discuss their advantages and disadvantages in relation to prenatal testing. We also discuss the factors to consider when implementing a microarray testing service for the diagnosis of fetal chromosomal aberrations. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Graphical abstract

545 KiB  
Review
Genetic Testing in the Diagnosis of Primary Ciliary Dyskinesia: State-of-the-Art and Future Perspectives
by Samuel A. Collins, Woolf T. Walker and Jane S. Lucas
J. Clin. Med. 2014, 3(2), 491-503; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020491 - 09 May 2014
Cited by 19 | Viewed by 7722
Abstract
Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive condition affecting around 1:15,000. In people with PCD, microscopic motile cilia do not move normally resulting in impaired clearance of mucus and debris leading to repeated sinopulmonary infection. If diagnosis is delayed, permanent bronchiectasis [...] Read more.
Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive condition affecting around 1:15,000. In people with PCD, microscopic motile cilia do not move normally resulting in impaired clearance of mucus and debris leading to repeated sinopulmonary infection. If diagnosis is delayed, permanent bronchiectasis and deterioration of lung function occurs. Other complications associated with PCD include congenital heart disease, hearing impairment and infertility. A small number of longitudinal studies suggest that lung function deteriorates before diagnosis of PCD but may stabilise following diagnosis with subsequent specialist management. Early diagnosis is therefore essential, but for a number of reasons referral for diagnostic testing is often delayed until older childhood or even adulthood. Functional diagnostic tests for PCD are expensive, time consuming and require specialist equipment and scientists. In the last few years, there have been considerable developments to identify genes associated with PCD, currently enabling 65% of patients to be identified by bi-allelic mutations. The rapid identification of new genes continues. This review will consider the evidence that early diagnosis of PCD is beneficial. It will review the recent advances in identification of PCD-associated genes and will discuss the role of genetic testing in PCD. It will then consider whether screening for PCD antenatally or in the new born is likely to become a feasible and acceptable for this rare disease. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Review
Beyond Trisomy 21: Additional Chromosomal Anomalies Detected through Routine Aneuploidy Screening
by Amy Metcalfe, Catriona Hippman, Melanie Pastuck and Jo-Ann Johnson
J. Clin. Med. 2014, 3(2), 388-415; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3020388 - 08 Apr 2014
Cited by 7 | Viewed by 9748
Abstract
Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other [...] Read more.
Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other than trisomy 21 with different prenatal screening tests. Non-invasive prenatal testing had the highest detection (DR) and lowest false positive (FPR) rates for trisomy 13 (DR: 90.3%; FPR: 0.2%), trisomy 18 (DR: 98.1%; FPR: 0.2%), and 45,X (DR: 92.2%; FPR: 0.1%); however, most estimates came from high-risk samples. The first trimester combined test also had high DRs for all conditions studied (trisomy 13 DR: 83.1%; FPR: 4.4%; trisomy 18 DR: 91.9%; FPR: 3.5%; 45,X DR: 70.1%; FPR: 5.4%; triploidy DR: 100%; FPR: 6.3%). Second trimester triple screening had the lowest DRs and highest FPRs for all conditions (trisomy 13 DR: 43.9%; FPR: 8.1%; trisomy 18 DR: 70.5%; FPR: 3.3%; 45,X DR: 77.2%; FPR: 9.3%). Prenatal screening tests differ in their ability to accurately detect chromosomal anomalies. Patients should be counseled about the ability of prenatal screening to detect anomalies other than trisomy 21 prior to undergoing screening. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Other

71 KiB  
Correction
Correction: Grömminger, S., et al. Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins. J. Clin. Med. 2014, 3, 679-692
by Sebastian Grömminger, Erbil Yagmur, Sanli Erkan, Sándor Nagy, Ulrike Schöck, Joachim Bonnet, Patricia Smerdka, Mathias Ehrich, Rolf-Dieter Wegner, Wera Hofmann and Markus Stumm
J. Clin. Med. 2014, 3(4), 1333-1334; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3041333 - 24 Nov 2014
Cited by 1 | Viewed by 5198
Abstract
The authors wish to make the following corrections to this paper [1]: On page 683 at the end of Section 3.2. lines 13–14, the word “no” is missing. The correct sentence should be: “There has been no evidence of false-negative NIPT results so [...] Read more.
The authors wish to make the following corrections to this paper [1]: On page 683 at the end of Section 3.2. lines 13–14, the word “no” is missing. The correct sentence should be: “There has been no evidence of false-negative NIPT results so far in the pregnancies included in this study.”[...] Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Letter
Carrier Screening: Past, Present, and Future
by Komal Bajaj and Susan J. Gross
J. Clin. Med. 2014, 3(3), 1033-1042; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3031033 - 15 Sep 2014
Cited by 26 | Viewed by 5863
Abstract
To date, preconceptual and prenatal patients have been offered gene-by-gene, disorder-by-disorder carrier screening. Newer techniques allow screening of many disorders at one time. The goal of this review is to provide an overview of the current practice and future direction of carrier screening [...] Read more.
To date, preconceptual and prenatal patients have been offered gene-by-gene, disorder-by-disorder carrier screening. Newer techniques allow screening of many disorders at one time. The goal of this review is to provide an overview of the current practice and future direction of carrier screening within the preconceptual/prenatal setting. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Case Report
Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins
by Sebastian Grömminger, Erbil Yagmur, Sanli Erkan, Sándor Nagy, Ulrike Schöck, Joachim Bonnet, Patricia Smerdka, Mathias Ehrich, Rolf-Dieter Wegner, Wera Hofmann and Markus Stumm
J. Clin. Med. 2014, 3(3), 679-692; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3030679 - 25 Jun 2014
Cited by 76 | Viewed by 15007 | Correction
Abstract
Non-invasive prenatal testing (NIPT) by random massively parallel sequencing of maternal plasma DNA for multiple pregnancies is a promising new option for prenatal care since conventional non-invasive screening for fetal trisomies 21, 18 and 13 has limitations and invasive diagnostic methods bear a [...] Read more.
Non-invasive prenatal testing (NIPT) by random massively parallel sequencing of maternal plasma DNA for multiple pregnancies is a promising new option for prenatal care since conventional non-invasive screening for fetal trisomies 21, 18 and 13 has limitations and invasive diagnostic methods bear a higher risk for procedure related fetal losses in the case of multiple gestations compared to singletons. In this study, in a retrospective blinded analysis of stored twin samples, all 16 samples have been determined correctly, with four trisomy 21 positive and 12 trisomy negative samples. In the prospective part of the study, 40 blood samples from women with multiple pregnancies have been analyzed (two triplets and 38 twins), with two correctly identified trisomy 21 cases, confirmed by karyotyping. The remaining 38 samples, including the two triplet pregnancies, had trisomy negative results. However, NIPT is also prone to quality issues in case of multiple gestations: the minimum total amount of cell-free fetal DNA must be higher to reach a comparable sensitivity and vanishing twins may cause results that do not represent the genetics of the living sibling, as described in two case reports. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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Graphical abstract

270 KiB  
Creative
Women’s Attitudes Regarding Prenatal Testing for a Range of Congenital Disorders of Varying Severity
by Mary E. Norton, Sanae Nakagawa and Miriam Kuppermann
J. Clin. Med. 2014, 3(1), 144-152; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm3010144 - 21 Jan 2014
Cited by 9 | Viewed by 7358
Abstract
Little is known about women’s comparative attitudes towards prenatal testing for different categories of genetic disorders. We interviewed women who delivered healthy infants within the past year and assessed attitudes towards prenatal screening and diagnostic testing, as well as pregnancy termination, for Down [...] Read more.
Little is known about women’s comparative attitudes towards prenatal testing for different categories of genetic disorders. We interviewed women who delivered healthy infants within the past year and assessed attitudes towards prenatal screening and diagnostic testing, as well as pregnancy termination, for Down syndrome (DS), fragile X (FraX), cystic fibrosis (CF), spinal muscular atrophy (SMA), phenylketonuria (PKU) and congenital heart defects (CHD). Ninety-five women aged 21 to 48 years participated, of whom 60% were Caucasian, 23% Asian, 10% Latina and 7% African American; 82% were college graduates. Ninety-five to ninety-eight percent indicated that they would have screening for each condition, and the majority would have amniocentesis (64% for PKU to 72% for SMA). Inclinations regarding pregnancy termination varied by condition: Whereas only 10% reported they would probably or definitely terminate a pregnancy for CHD, 41% indicated they would do so for DS and 62% for SMA. Most women in this cohort reported that they would undergo screening for all six conditions presented, the majority without the intent to terminate an affected pregnancy. These women were least inclined to terminate treatable disorders (PKU, CHD) versus those associated with intellectual disability (DS, FraX) and were most likely to terminate for SMA, typically lethal in childhood. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
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