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Siegel MR, James K, Bromley B, Koelper NC, Chasen ST, Griffin L, Roman AS, Limaye M, Ranzini A, Clifford C, Biggio JR, Subramaniam A, Seasely AR, Page JM, Nicholas SS, Idler J, Rao R, Shree R, McLennan G, Dugoff L, Twin cfDNA Study Consortium. First-Trimester Cell-Free DNA Fetal Fraction and Birth Weight in Twin Pregnancies. Am J Perinatol 2025; 42:605-611. [PMID: 39260415 DOI: 10.1055/a-2413-2353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
The relationship between fetal fraction and birth weight in twin gestations is poorly understood. This study aimed to investigate the relationship between first-trimester cell-free DNA (cfDNA) fetal fraction and birth weight <10th percentile in twin gestations.This is a planned secondary analysis of the Twin cfDNA Study, a 17-center retrospective cohort of twin pregnancies screened for aneuploidy using cfDNA in the first trimester from December 2011 to February 2022, excluding those with positive screen results for chromosomal aneuploidy. cfDNA testing was performed by a single laboratory using massively parallel sequencing. Baseline characteristics and birth weight of pregnancies with normal fetal fraction were compared with those with low (<5%) and high (>95%) fetal fraction using univariable analyses and multivariable regression.A total of 1,041 twin pregnancies were included. Chronic hypertension, elevated body mass index, and self-identified Black race were associated with fetal fraction <5th percentile. There was no difference in median fetal fraction between those with birth weight <10th percentile in at least one twin (median [interquartile range (IQR)] fetal fraction: 12.2% [9.8, 14.8] vs. those with normal birth weight (≥10th percentile) in both twins (median [IQR] fetal fraction: 12.3% [9.7, 15.2] for normal birth weight, p = 0.49). There was no association between high or low fetal fraction and birth weight <10th percentile for one (p = 0.45) or both (p = 0.81) twins, and there was no association between high or low fetal fraction and birth weight <5th percentile for one (p = 0.44) or both (p = 0.74) twins. The results were unchanged after adjustment for potential confounders.In this large cohort, there was no association between the extremes of cfDNA fetal fraction and birth weight <10th percentile, suggesting that first-trimester fetal fraction may not predict impaired fetal growth in twin gestations. · No association between fetal fraction and small for gestational age birth weight in twins.. · Results suggest that fetal fraction does not predict birth weight in twin gestations.. · These results differ from the relationship between fetal fraction and birth weight in singletons..
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Affiliation(s)
- Molly R Siegel
- Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kaitlyn James
- Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts
| | - Bryann Bromley
- Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts
| | - Nathanael C Koelper
- Department of Obstetrics and Gynecology, Women's Health Clinical Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephen T Chasen
- Division of Maternal-Fetal Medicine, Weill Cornell Medical College, New York, New York
| | - Laurie Griffin
- Department of Obstetrics and Gynecology, The Warren Alpert Medical School at Brown University, Providence, Rhode Island
| | - Ashley S Roman
- Department of Obstetrics and Gynecology, NYU Grossman School of Medicine, New York, New York
| | - Meghana Limaye
- Department of Obstetrics and Gynecology, NYU Grossman School of Medicine, New York, New York
| | - Angela Ranzini
- Division of Maternal-Fetal Medicine, MetroHealth, Cleveland, Ohio
| | - Caitlin Clifford
- Division of Maternal-Fetal Medicine, University of Michigan Health, Ann Arbor, Michigan
| | - Joseph R Biggio
- Division of Maternal-Fetal Medicine, Ochsner Health, New Orleans, Louisiana
| | - Akila Subramaniam
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
| | - Angela R Seasely
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
| | - Jessica M Page
- Division of Maternal-Fetal Medicine, Intermountain Health, Salt Lake City, Utah
| | - Sara S Nicholas
- Axia Women's Health Main Line Perinatal Associates, Wynnewood, Pennsylvania
| | - Jay Idler
- Division of Maternal-Fetal Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Rashmi Rao
- Department of Obstetrics and Gynecology, UCLA, Los Angeles, California
| | - Raj Shree
- Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
| | - Graham McLennan
- Clinical Affairs, Sequenom Inc, LabCorp, San Diego, California
| | - Lorraine Dugoff
- Division of Reproductive Genetics, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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Peng H, Li X, Zeng L, Wang Y, Wang Y, Qin C, Chen Y. Reciprocal relationship between abortion stigma and depressive symptoms among women who underwent termination of pregnancy for fetal anomalies: a cross-lagged panel study. BMC Pregnancy Childbirth 2025; 25:246. [PMID: 40055664 PMCID: PMC11887342 DOI: 10.1186/s12884-025-07376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 02/25/2025] [Indexed: 04/11/2025] Open
Abstract
INTRODUCTION This study aimed to examine the interactions between abortion stigma and depressive symptoms among women who underwent termination of pregnancy for fetal anomalies over time. METHODS This study is a longitudinal, observational study with two measurement points. A total of 241 women with fetal anomalies filled out the Individual Level Abortion Stigma Scale and the Edinburgh Postnatal Depression Scale before and after terminating pregnancy. Cross-lagged panel analysis was conducted to analyze the interactions between abortion stigma and depressive symptoms over time. RESULTS The level of abortion stigma before terminating pregnancy positively influenced depressive symptoms after terminating pregnancy (β = 0.12, P < 0.05). The depressive symptoms before terminating pregnancy positively influenced the level of abortion stigma after terminating pregnancy(β = 0.08, P < 0.05). CONCLUSIONS Abortion stigma and depressive symptoms before terminating pregnancy should be evaluated, and comprehensive intervention must be taken to alleviate them. Healthcare professionals need to pay attention to the reciprocal relationships between abortion stigma and depressive symptoms and seek intervention to reduce both.
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Affiliation(s)
- Huiting Peng
- Department of Nursing, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Department of Gynecology, Hunan Maternal and Child Health Hospital, Changsha, 410008, China
| | - Xi Li
- The First Affiliated Hospital of Hunan College of TCM, Zhuzhou, 412000, China
| | - Lihong Zeng
- Xiangya School of Nursing, Central South University, Changsha, 410013, China
| | - Ying Wang
- Xiangya School of Nursing, Central South University, Changsha, 410013, China
| | - Yaohan Wang
- Xiangya School of Nursing, Central South University, Changsha, 410013, China
| | - Chunxiang Qin
- Department of Nursing, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
- Health management Medicine Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Yang Chen
- Department of Nursing, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
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Gallois H, Ravitsky V, Roy MC, Laberge AM. Defining ethical criteria to guide the expanded use of Noninvasive Prenatal Screening (NIPS): Lessons about severity from preimplantation genetic testing. Eur J Hum Genet 2025; 33:167-175. [PMID: 39462080 PMCID: PMC11840150 DOI: 10.1038/s41431-024-01714-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 09/09/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
We hypothesized that ethical criteria that guide the use of preimplantation genetic testing (PGT) could be used to inform policies about expanded use of non-invasive prenatal screening (NIPS). We used a systematic review of reasons approach to assess ethical criteria used to justify using (or not using) PGT for genetic conditions. Out of 1135 identified documents, we retained and analyzed 216 relevant documents. Results show a clear distinction in acceptability of PGT for medical vs. non-medical conditions. Criteria to decide on use of PGT for medical conditions are largely based on their severity, but there is no clear definition of "severity". Instead, characteristics of the condition that relate to severity are used as sub-criteria to assess severity. We found that characteristics that are used as sub-criteria for assessing severity include monogenic etiology, high penetrance, absence of treatment, early age of onset, shortened lifespan, and reduced quality of life. Consensus about the use of PGT is highest for conditions that meet most of these criteria. There is no consensus around the acceptability of using PGT to detect non-medical conditions. We propose that the same severity criteria could be used by policymakers to assess the acceptability of using other genetic tests in screening and practice, including for the use of NIPS for additional conditions as indications broaden.
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Affiliation(s)
- Hortense Gallois
- Simon Fraser University, Vancouver, BC, Canada
- Bioethics, Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montreal, QC, Canada
| | - Vardit Ravitsky
- Bioethics, Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montreal, QC, Canada
- President and CEO, The Hastings Center, Garrison, New York, USA
| | - Marie-Christine Roy
- Bioethics, Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montreal, QC, Canada
| | - Anne-Marie Laberge
- Bioethics, Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montreal, QC, Canada.
- Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada.
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Quebec, Montreal, Canada.
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Yang L, Yang J, Bu G, Han R, Rezhake J, La X. Efficiency of Non-Invasive Prenatal Testing in Detecting Fetal Copy Number Variation: A Retrospective Cohort Study. Int J Womens Health 2024; 16:1661-1669. [PMID: 39381715 PMCID: PMC11460342 DOI: 10.2147/ijwh.s479747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/25/2024] [Indexed: 10/10/2024] Open
Abstract
Purpose Screening of pathological copy number variations (CNVs) is important for early-diagnosis of hereditary disease. This study was designed to investigate the efficiency of non-invasive prenatal testing (NIPT) in detecting fetal CNVs. Methods This retrospective analysis included fetuses with CNVs between January 2018 and December 2020. Karyotype analysis and CNV sequencing (CNV-seq) were performed. We then analyzed the positive predictive values of the subchromosomal microdeletions and microduplications. Results Fifty-eight subjects with aberrant CNVs were screened after NIPT, among which 44 finally underwent amniocentesis. CNV-seq confirmed the presence of CNVs in 24 cases. This indicated that false positivity rate of NIPT was 45.5%. Among 24 cases with CNVs after CNV-seq, only 4 showed consistent findings with karyotype analysis, which showed that karyotyping analysis yielded a missed diagnosis rate of 83.3% for the genome CNV. Positive predictive value (PPV) was 50.0% for CNVs with a length of <5 Mb after NIPT screening. PPV for CNVs with a length of 5 Mb-10 Mb was 33.3%, while that for CNVs with a length of ≥10Mb was 60%. For CNVs duplication after NIPT, the PPV was 65.2%, while that for deletion was 36.4%. Conclusion For CNVs detected after NIPT, it should be combined with ultrasonographic findings, karyotype analysis, CNV-seq or CMA to determine the pregnancy outcome. Expanding NIPT may increase the risk of unnecessary invasive surgery and unintended selective termination of pregnancy.
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Affiliation(s)
- Li Yang
- Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China
| | - Jing Yang
- Department of Gynaecology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China
| | - Guosen Bu
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China
| | - Rui Han
- Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China
| | - Jiamila Rezhake
- Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China
| | - Xiaolin La
- Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China
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Mattar CN, Chew WL, Lai PS. Embryo and fetal gene editing: Technical challenges and progress toward clinical applications. Mol Ther Methods Clin Dev 2024; 32:101229. [PMID: 38533521 PMCID: PMC10963250 DOI: 10.1016/j.omtm.2024.101229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Gene modification therapies (GMTs) are slowly but steadily making progress toward clinical application. As the majority of rare diseases have an identified genetic cause, and as rare diseases collectively affect 5% of the global population, it is increasingly important to devise gene correction strategies to address the root causes of the most devastating of these diseases and to provide access to these novel therapies to the most affected populations. The main barriers to providing greater access to GMTs continue to be the prohibitive cost of developing these novel drugs at clinically relevant doses, subtherapeutic effects, and toxicity related to the specific agents or high doses required. In vivo strategy and treating younger patients at an earlier course of their disease could lower these barriers. Although currently regarded as niche specialties, prenatal and preconception GMTs offer a robust solution to some of these barriers. Indeed, treating either the fetus or embryo benefits from economy of scale, targeting pre-pathological tissues in the fetus prior to full pathogenesis, or increasing the likelihood of complete tissue targeting by correcting pluripotent embryonic cells. Here, we review advances in embryo and fetal GMTs and discuss requirements for clinical application.
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Affiliation(s)
- Citra N.Z. Mattar
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 12, Singapore, Singapore 119228
- Department of Obstetrics and Gynaecology, National University Health System, Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 12, Singapore, Singapore 119228
| | - Wei Leong Chew
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, 60 Biopolis St, Singapore, Singapore 138672
| | - Poh San Lai
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 12, Singapore, Singapore 119228
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Eltabbakh N, Mohasin Y, Jeddy R. Advancements of non-invasive prenatal testing: the role of obstetricians. Front Med (Lausanne) 2024; 11:1388481. [PMID: 38938382 PMCID: PMC11208619 DOI: 10.3389/fmed.2024.1388481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/20/2024] [Indexed: 06/29/2024] Open
Abstract
Since its debut in 2011, Non-Invasive Prenatal Testing (NIPT) has continually demonstrated its effectiveness in detecting an expanding number of diseases. NIPT offers a less invasive approach to prenatal chromosomal disease screening, providing prospective parents with vital information to better prepare for their potential pregnancy outcomes. NIPT was primarily designed for screening trisomy 13, 18, and 21. However, its scope has since broadened to encompass microdeletions and autosomal dominant monogenic diseases. Conversely, the normalization of NIPT can have unintended consequences. Some patients opt for NIPT without any medical indications, driven by a desire to remain cautious. This over-screening for chromosomal abnormalities can exacerbate pregnancy-related anxiety, as individuals might feel pressured into taking the test unnecessarily. While NIPT can be highly successful when conducted correctly, it is not infallible, and obstetricians play a crucial role in managing patient expectations. This includes providing genetic counseling to individuals with relevant genetic information regarding their personal and family histories. In the context of NIPT, a bioinformatics analysis is performed on a cell-free DNA (cfDNA) sample extracted from the mother's placenta to determine the fetal fraction (FF). This FF measurement is vital for quality control and ensuring statistical confidence in the test results. Raising awareness among clinicians about the significance of FF enhances patient care and alleviate concerns about the possibility of failed NIPT. This paper aims to explore the ongoing debates and more specifically the significance and pitfalls of NIPT on a psychosocial and ethical scale, all while highlighting the importance of genetic counseling.
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Affiliation(s)
- Nada Eltabbakh
- Royal College of Surgeons in Ireland (Bahrain), Muharraq, Bahrain
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Liang Y, Li M, Fei J, Chen Z. Should non-invasive prenatal testing be recommended for patients who achieve pregnancy with PGT? BMC Pregnancy Childbirth 2024; 24:100. [PMID: 38302865 PMCID: PMC10832195 DOI: 10.1186/s12884-024-06284-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/21/2024] [Indexed: 02/03/2024] Open
Abstract
OBJECTIVE To determine whether non-invasive prenatal testing is an alternative testing option to preimplantation genetic testing (PGT) in pregnant patients. METHODS This was a retrospective study of the clinical outcomes of patients who underwent PGT and invasive or non-invasive pregnancy testing after euploid blastocyst transfer at our IVF centre between January 2017 and December 2022. RESULTS In total, 321 patients were enrolled in this study, 138 (43.0%) received invasive pregnancy testing, and 183 (57.0%) patients underwent non-invasive testing. The mean age of the patients in Group 2 was higher than that of the patients in Group 1 (35.64 ± 4.74 vs. 31.04 ± 4.15 years, P < 0.001). The basal LH and AMH levels were higher in Group 1 than in Group 2 (4.30 ± 2.68 vs. 3.40 ± 1.88, P = 0.003; 5.55 ± 11.22 vs. 4.09 ± 3.55, P = 0.012), but the clinical outcomes were not significantly different. Furthermore, the clinical outcomes of patients undergoing invasive testing were similar to those of patients undergoing non-invasive testing with the same PGT indication. CONCLUSION Our results suggest that non-invasive pregnancy testing is a suitable alternative option for detecting the foetal chromosomal status in a PGT cycle. However, the usefulness of non-invasive testing in PGT-M patients is still limited.
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Affiliation(s)
- Yunhao Liang
- Center of Reproductive Medicine, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, CN, China
| | - Meiyi Li
- Center of Reproductive Medicine, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, CN, China
| | - Jia Fei
- Peking Jabrehoo Med Tech Co., Ltd, Beijing, CN, China
| | - Zhiheng Chen
- Center of Reproductive Medicine, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, CN, China.
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Li Y, Yang X, Zhang Y, Lou H, Wu M, Liu F, Chang W, Zhao X. The detection efficacy of noninvasive prenatal genetic testing (NIPT) for sex chromosome abnormalities and copy number variation and its differentiation in pregnant women of different ages. Heliyon 2024; 10:e24155. [PMID: 38293423 PMCID: PMC10826137 DOI: 10.1016/j.heliyon.2024.e24155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/15/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Objective To analyze the efficacy of noninvasive prenatal genetic testing (NIPT) in detecting fetal sex chromosome abnormalities and copy number variation (CNV), compare the efficacy between NIPT and serological screening alone, and further analyze the fetal sex chromosome abnormalities and CNV differentiation in pregnant women of different ages, so as to provide a reference for the prevention and control of fetal birth defects. Methods Clinical data from 22,692 pregnant women admitted to our hospital from January 2013 to December 2022 were retrospectively analyzed. All participants underwent serological screening and NIPT screening to compare fetal chromosomal abnormalities between the two screening modalities. 145 women whose fetus were diagnosed as sex chromosome abnormalities and 36 women whose fetus were diagnosed as CNV abnormalities based on NIPT screening were selected for prenatal diagnosis by amniocentesis or karyotyping. Taking prenatal diagnosis as the standard, the four-grid table method was used to detect the positive predictive value of NIPT screening for fetal sex chromosomal abnormalities and CNV. According to the age, pregnant women were divided into 18-30 years old (n = 9844), 31-35 years old (n = 7612), >35 years old (n = 5236), and then the detection rates of sexual fetal chromosomal abnormalities, CNV and total chromosomal abnormalities were compared in pregnant women. Results Among the 22,692 pregnant women in this study, the high-risk proportion of serologic screening with 4.38% was higher than that of NIPT screening with 1.93% (P < 0.05). Among the 145 women with fetal sex chromosome abnormalities screened by NIPT, 122 cases of fetal sex chromosome abnormalities were diagnosed prenatally, including 45, X/47, XXX/47, XYY/47, XXY. The positive predictive values of NIPT screening were 25.00%, 58.82%, 85.71%, and 85.71%, respectively, with an overall predictive value of 44.26%. The positive predictive value of fetal sex chromosome abnormalities in NIPT screening was higher than that of serological screening (P < 0.05). Among the 36 pregnant women with fetal CNV, NIPT screening showed that CNVs≤10 Mb and CNVs>10 Mb were 33.33% and 66.67%, respectively. There were 12 cases of prenatal diagnosis of fetal CNV, among which the NIPT-screened positive predictive values of fetal copy number deletion, duplicate, deletion and duplicate were 50.00%, 57.14% and 100.00%, respectively, with an overall predictive value of 58.33%. The positive predictive value of CNV in NIPT screening was higher than that of serological screening without statistically significant difference (P > 0.05). The results of NIPT screening showed that the detection rate of fetal sex chromosome abnormalities and total abnormalities of pregnant women over 35 years of age was significantly higher than that of pregnant women aged 18-30 and 31-35 years (P < 0.05). Conclusion NIPT screening could greatly improve the detection efficacy of fetal sex chromosome abnormalities, CNV and other chromosome abnormalities, and decline the false positive rate. However, the positive predictive value of NIPT screening was relatively low, and further prenatal testing and genetic counseling are still required. In addition, NIPT screening for fetal sex chromosome abnormalities, and the detection rate of total abnormalities in pregnant women older than 35 years old were increased significantly, and pregnancy at an advanced age may be one of the risk factors for fetal chromosomal abnormalities.
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Affiliation(s)
- Yimei Li
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Xiaofeng Yang
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Ying Zhang
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Huan Lou
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Mingli Wu
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Fang Liu
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Wenjing Chang
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
| | - Xueling Zhao
- Department of Gynecology and Obstetrics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000, Henan, PR China
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Ongie L, Raj HA, Stevens KB. Genetic Counseling and Family Screening Recommendations in Patients with Telomere Biology Disorders. Curr Hematol Malig Rep 2023; 18:273-283. [PMID: 37787873 DOI: 10.1007/s11899-023-00713-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2023] [Indexed: 10/04/2023]
Abstract
PURPOSE OF REVIEW Telomere biology disorders (TBDs) encompass a spectrum of genetic diseases with a common pathogenesis of defects in telomerase function and telomere maintenance causing extremely short telomere lengths. Here, we review the current literature surrounding genetic testing strategies, cascade testing, reproductive implications, and the role of genetic counseling. RECENT FINDINGS The understanding of the genetic causes and clinical symptoms of TBDs continues to expand while genetic testing and telomere length testing are nuanced tools utilized in the diagnosis of this condition. Access to genetic counseling is becoming more abundant and is valuable in supporting patients and their families in making informed decisions. Patient resources and support groups are valuable to this community. Defining which populations should be offered genetic counseling and testing is imperative to provide proper diagnoses and medical management for not only the primary patient, but also their biological relatives.
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Affiliation(s)
| | - Hannah A Raj
- Team Telomere, Inc., New York, NY, USA
- College of Medicine, University of Illinois, Chicago, IL, USA
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Lee HYD, Chan LW. Evaluation of pre-test counselling offered for non-invasive prenatal testing (NIPT) as a primary screening tool. J OBSTET GYNAECOL 2023; 43:2204959. [PMID: 37154788 DOI: 10.1080/01443615.2023.2204959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
The increasing popularity and expansion of non-invasive prenatal testing (NIPT) to screen for rare conditions beyond common trisomies prompts evaluation of pre-test counselling currently offered. We conducted a prospective survey to assess women's knowledge of NIPT in those who had undergone NIPT (study group) and those who were planning to have NIPT (control group). Out of the 189 questionnaires analysed, the study group did not show a higher knowledge score compared to the control group (P = 0.097). 44% misunderstood that NIPT can identify more conditions than invasive testing, 69.8% were unaware of the recommended need for nuchal translucency measurement and 52.6% were unaware of the possibility of incidental findings. 31% even considered discussing termination of pregnancy as one of the next steps if NIPT shows high risk for Down syndrome. This study shows that current pre-test counselling is inadequate. Service providers should address these knowledge gaps and assist women to make informed choices.Impact StatementWhat is already known on this subject? Pre-test counselling for non-invasive prenatal testing (NIPT) should be conducted to assist women in making an informed consent.What do the results of this study add? Our results show that a significant proportion of women are unaware of the limitations of NIPT.What are the implications of these findings for clinical practice and/or further research? Service providers should improve their pre-test counselling focusing on areas of knowledge deficiencies and misunderstanding on NIPT identified in this study.
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Affiliation(s)
- Ho Yin Diana Lee
- Department of Obstetrics and Gynaecology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
| | - Lin Wai Chan
- Department of Obstetrics and Gynaecology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
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Abstract
Noninvasive prenatal screening with cell-free DNA is now considered a first-line screening for common aneuploidies. Advancements in existing laboratory techniques now allow to interrogate the entirety of the fetal genome, and many commercial laboratories have expanded their screening panels to include screening for rare autosomal aneuploidies and copy number variants. Here, we review the currently available data on the performance of fetal cell-free DNA to detect rare autosomal aneuploidies and copy number variants that are associated with clinically significant microdeletion and microduplication syndromes and the current position of medical societies on routine screening for these syndromes.
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Affiliation(s)
- Desiree Fiorentino
- Division of Fetal Medicine, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
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Dunn TM, Subramaniam A. Updates in Genetic Screening for the General Obstetrician. Obstet Gynecol Clin North Am 2023; 50:493-507. [PMID: 37500212 DOI: 10.1016/j.ogc.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
The number of prenatal genetic screening options, including aneuploidy screening and carrier screening, has drastically increased with rapid advancements in DNA sequencing technologies. Noninvasive prenatal screening analyzing cell-free DNA has quickly been integrated into routine prenatal care as it is the most sensitive and specific screening method for pregnancies at increased and average risk of fetal aneuploidy. The aim of this article is to outline current recommendations for cell-free DNA screening and carrier screening, important aspects of pretest and posttest counseling for obstetric providers, and which patients should be referred to a genetic specialist.
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Affiliation(s)
- Taylor M Dunn
- Department of Genetics, University of Alabama at Birmingham, 1720 2nd Avenue South, VH1L108B, Birmingham, AL 35294-0019, USA.
| | - Akila Subramaniam
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 1700 6th Avenue South, Women and Infants Center, 10270, Birmingham, AL 35249, USA
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Chen L, Wang L, Zeng Y, Yin D, Tang F, Xie D, Zhu H, Liu H, Wang J. Defining the scope of extended NIPS in Western China: evidence from a large cohort of fetuses with normal ultrasound scans. BMC Pregnancy Childbirth 2023; 23:593. [PMID: 37598172 PMCID: PMC10439619 DOI: 10.1186/s12884-023-05921-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 08/14/2023] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Standard noninvasive prenatal screening(NIPS) is an accurate and reliable method to screen for common chromosome aneuploidies, such as trisomy 21, 18 and 13. Extended NIPS has been used in clinic for not only aneuploidies but also copy number variants(CNVs). Here we aim to define the range of chromosomal abnormalities that should be able to identify by NIPS in order to be an efficient extended screening test for chromosomal abnormalities. METHODS A prospective study was conducted, involving pregnant women without fetal sonographic structural abnormalities who underwent amniocentesis. Prenatal samples were analyzed using copy number variation sequencing(CNV-seq) to identify fetal chromosomal abnormalities. RESULTS Of 28,469 pregnancies included 1,022 (3.59%) were identified with clinically significant fetal chromosome abnormalities, including 587 aneuploidies (2.06%) and 435 (1.53%) pathogenic (P) / likely pathogenic (LP) CNVs. P/LP CNVs were found in all chromosomes, but the distribution was not uniform. Among them, P/LP CNVs in chromosomes 16, 22, and X exhibited the highest frequencies. In addition, P/LP CNVs were most common on distal ends of the chromosomes and in low copy repeat regions. Recurrent microdeletion/microduplication syndromes (MMS) accounted for 40.69% of total P/LP CNVs. The size of most P/LP CNVs (77.47%) was < 3 Mb. CONCLUSIONS In addition to aneuploidies, the scope of extended NIPS should include the currently known P/LP CNVs, especially the regions with recurrent MMS loci, distal ends of the chromosomes, and low copy repeat regions. To be effective detection should include CNVs of < 3 Mb. Meanwhile, sufficient preclinical validation is still needed to ensure the clinical effect of extended NIPS.
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Affiliation(s)
- Lin Chen
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Li Wang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Yang Zeng
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Daishu Yin
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Feng Tang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Dan Xie
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Hongmei Zhu
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Hongqian Liu
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Block 3 No. 20, Ren Min Nan Road, Wuhou district, 610041, Chengdu, China
| | - Jing Wang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Block 3 No. 20, Ren Min Nan Road, Wuhou district, 610041, Chengdu, China.
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Lledo B, Morales R, Antonio Ortiz J, Bernabeu A, Bernabeu R. Noninvasive preimplantation genetic testing using the embryo spent culture medium: an update. Curr Opin Obstet Gynecol 2023; 35:294-299. [PMID: 37144571 DOI: 10.1097/gco.0000000000000881] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
PURPOSE OF REVIEW The presence of cell-free DNA (cf-DNA) in the embryo spent culture medium allows to develop a noninvasive PGT-A (niPGTA). Noninvasive PGT-A may provide a simpler, safer and less costly approach to preimplantation genetic testing of aneuploidy (PGT-A). Furthermore, niPGTA would provide wider access to embryo genetic analysis and circumvent many legal and ethical considerations. However, the concordance rate between the results obtained by PGT-A and niPGTA varies among studies and, their clinical utility has not been already demonstrated. This review evaluates the niPGTA reliability based on SCM and adds new knowledge about the clinical relevance of SCM for noninvasive PGT-A. RECENT FINDINGS The most recent concordance studies evaluating the accuracy of niPGTA using SCM showed a high variation in the informativity rate of SCM and the diagnostic concordance. Also, sensitivity and specificity showed similar heterogeneous results. Therefore, these results do not support the clinical utility of niPGTA. Regarding clinical outcome, the data are initial and further research, including randomized and nonselection studies are needed. SUMMARY Further research, including randomized and nonselection studies, as well as optimization of embryo culture conditions and medium retrieval, are needed to improve the reliability and clinical utility of niPGTA.
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Affiliation(s)
| | | | | | - Andrea Bernabeu
- Instituto Bernabeu of Fertility and Gynaecology
- Chair of Community Medicine and Reproductive Health, Miguel Hernández University, Alicante, Spain
| | - Rafael Bernabeu
- Instituto Bernabeu of Fertility and Gynaecology
- Chair of Community Medicine and Reproductive Health, Miguel Hernández University, Alicante, Spain
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Dardik R, Janczar S, Lalezari S, Avishai E, Levy-Mendelovich S, Barg AA, Martinowitz U, Babol-Pokora K, Mlynarski W, Kenet G. Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions. Int J Mol Sci 2023; 24:11846. [PMID: 37511607 PMCID: PMC10380558 DOI: 10.3390/ijms241411846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/09/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.
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Affiliation(s)
- Rima Dardik
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
| | - Szymon Janczar
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Shadan Lalezari
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
| | - Einat Avishai
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
| | - Sarina Levy-Mendelovich
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
| | - Assaf Arie Barg
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
| | - Uri Martinowitz
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
| | - Katarzyna Babol-Pokora
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Wojciech Mlynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Gili Kenet
- National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
- Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel
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16
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Maya I, Salzer Sheelo L, Brabbing-Goldstein D, Matar R, Kahana S, Agmon-Fishman I, Klein C, Gurevitch M, Basel-Salmon L, Sagi-Dain L. Clinical utility of expanded non-invasive prenatal screening compared with chromosomal microarray analysis in over 8000 pregnancies without major structural anomaly. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2023; 61:698-704. [PMID: 36776119 DOI: 10.1002/uog.26177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 01/01/2023] [Accepted: 01/27/2023] [Indexed: 06/03/2023]
Abstract
OBJECTIVES To evaluate the theoretical added value of two types of non-invasive prenatal screening (NIPS) expansions in pregnancies without major structural anomalies over the commonly used NIPS for chromosomes 13, 18, 21, X and Y (5-NIPS) and to compare them with the added value of chromosomal microarray analysis (CMA). METHODS This was a retrospective cohort study based on CMA results of all pregnancies with normal ultrasound (including pregnancies with soft markers and with abnormal maternal serum screening) that had undergone amniocentesis between January 2013 to February 2022 and were registered in the database of the Rabin Medical Center genetic laboratory. We calculated the theoretical yield of 5-NIPS and compared the added value of expanded 5-NIPS for common microdeletions (1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1 and 22q11.2) and genome-wide NIPS (including variants > 5 Mb) with the added value of CMA in the overall cohort and in subgroups according to indication for invasive testing. RESULTS Among the 8605 examined pregnancies, 122 (1.4%) clinically significant CMA results were demonstrated. Of these, 44 (36.1%) were theoretically detectable on 5-NIPS, with the rates of 1.56% in 642 pregnancies with abnormal maternal serum screening, 0.63% in 318 pregnancies with soft markers, 0.62% in 4378 women with advanced maternal age (≥ 35 years) and 0.15% in 3267 women younger than 35 years. In addition to aneuploidies detectable on 5-NIPS, three (0.03%) cases detectable on 5-NIPS expanded for common microdeletions and nine (0.10%) cases detectable on genome-wide NIPS (excluding common microdeletions) were identified in the overall cohort. The added value of expanded NIPS tools over 5-NIPS was significantly lower compared with that of CMA, for the overall cohort and subgroups. CONCLUSIONS 5-NIPS and even genome-wide NIPS would miss 63.9% and 54.1% of clinically significant CMA findings, respectively. The added value of 5-NIPS expanded to detect common microdeletions over 5-NIPS is about 0.035%, and the overall added value of genome-wide NIPS aimed at large CNVs is about 0.14%, both much lower compared with the added value of CMA (0.91%). These findings should assist healthcare practitioners in guiding couples towards informed decision-making regarding the choice between prenatal invasive testing and NIPS. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
- I Maya
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - L Salzer Sheelo
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - D Brabbing-Goldstein
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - R Matar
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - S Kahana
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - I Agmon-Fishman
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - C Klein
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - M Gurevitch
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
| | - L Basel-Salmon
- Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - L Sagi-Dain
- Genetics Institute, Carmel Medical Center, affiliated to the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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17
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Parisi MA, Caggana M, Cohen JL, Gold NB, Morris JA, Orsini JJ, Urv TK, Wasserstein MP. When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2023; 193:44-55. [PMID: 36876995 PMCID: PMC10475244 DOI: 10.1002/ajmg.c.32036] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 01/10/2023] [Accepted: 01/21/2023] [Indexed: 03/07/2023]
Abstract
This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.
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Affiliation(s)
- Melissa A Parisi
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Michele Caggana
- Wadsworth Center, New York State Department of Health, Division of Genetics, Albany, New York, USA
| | | | - Nina B Gold
- Massachusetts General Hospital for Children, Boston, Massachusetts, USA
| | - Jill A Morris
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Joseph J Orsini
- New York State Department of Health, Wadsworth Center, Albany, New York, USA
| | - Tiina K Urv
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA
| | - Melissa P Wasserstein
- Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, New York, USA
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Predicting Genetic Disorder and Types of Disorder Using Chain Classifier Approach. Genes (Basel) 2022; 14:genes14010071. [PMID: 36672812 PMCID: PMC9858679 DOI: 10.3390/genes14010071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/16/2022] [Accepted: 12/16/2022] [Indexed: 12/28/2022] Open
Abstract
Genetic disorders are the result of mutation in the deoxyribonucleic acid (DNA) sequence which can be developed or inherited from parents. Such mutations may lead to fatal diseases such as Alzheimer's, cancer, Hemochromatosis, etc. Recently, the use of artificial intelligence-based methods has shown superb success in the prediction and prognosis of different diseases. The potential of such methods can be utilized to predict genetic disorders at an early stage using the genome data for timely treatment. This study focuses on the multi-label multi-class problem and makes two major contributions to genetic disorder prediction. A novel feature engineering approach is proposed where the class probabilities from an extra tree (ET) and random forest (RF) are joined to make a feature set for model training. Secondly, the study utilizes the classifier chain approach where multiple classifiers are joined in a chain and the predictions from all the preceding classifiers are used by the conceding classifiers to make the final prediction. Because of the multi-label multi-class data, macro accuracy, Hamming loss, and α-evaluation score are used to evaluate the performance. Results suggest that extreme gradient boosting (XGB) produces the best scores with a 92% α-evaluation score and a 84% macro accuracy score. The performance of XGB is much better than state-of-the-art approaches, in terms of both performance and computational complexity.
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Abstract
PURPOSE OF REVIEW Prenatal genetic testing can be divided into two categories: screening and diagnostic. This article will focus on reviewing prenatal genetic screening tests. RECENT FINDINGS Cell-free DNA (cfDNA) is a new prenatal genetic screening test with a high degree of accuracy for identifying certain genetic conditions like trisomy 21, 18, and 13. However, cfDNA has also been applied in the screening of other genetic conditions without similar research support. SUMMARY Prenatal genetic screening evaluates at risk pregnancies - including both carrier screening, which can be done at any point in a person's life, and aneuploidy screening, which is done during pregnancy. Within screening, there is a new noninvasive technology that has revolutionized prenatal screening called cfDNA testing. Compared to previous methods, this technology is easier to administer and more accurate for certain genetic conditions. However, cfDNA has also been applied to test for less common genetic conditions without efficacious research support. In this time of expansion in genetic testing, it is important that providers educate themselves on the research support behind each type of genetic test. It is vital that professional organizations continuously update their testing approach to match these rapidly evolving technologies and the patient population they serve.
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Affiliation(s)
- Morgan Jenkins
- University of Alabama at Birmingham Heersink School of Medicine
| | - Angela R Seasely
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Akila Subramaniam
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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21
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Li Z, Lai GR. Discrepancy between non-invasive prenatal testing result and fetal karyotype caused by rare confined placental mosaicism: A case report. World J Clin Cases 2022; 10:8641-8647. [PMID: 36157819 PMCID: PMC9453383 DOI: 10.12998/wjcc.v10.i24.8641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 06/01/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Confined placental mosaicism (CPM) is one of the major reasons for discrepancies between the results of non-invasive prenatal testing (NIPT) and fetal karyotype analysis.
CASE SUMMARY We encountered a primiparous singleton pregnant woman with a rare CPM consisting of 47,XY,+21; 47,XXY; and 46,XY, who obtained a false-positive result on NIPT with a high risk for trisomy 21. Copy-number variation sequencing on amniotic fluid cells, fetal tissue, and placental biopsies showed that the fetal karyotype was 47,XXY, while the placenta was a rare mosaic of 47,XY,+21; 47,XXY; and 46,XY.
CONCLUSION The patient had a rare CPM consisting of 47,XY,+21; 47,XXY; and 46,XY, which caused a discrepancy between the result of NIPT and the actual fetal karyotype. It is important to remember that NIPT is a screening test, not a diagnostic test. Any positive result should be confirmed with invasive testing, and routine ultrasound examination is still necessary after a negative result.
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Affiliation(s)
- Zhen Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Guang-Rui Lai
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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22
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Akiel MA, Mohamud MS, Masuadi EM, Alamri HS. Knowledge and attitude of pregnant women in the Kingdom of Saudi Arabia toward Noninvasive prenatal testing: A single center study. Mol Genet Genomic Med 2022; 10:e1960. [PMID: 35481946 PMCID: PMC9266591 DOI: 10.1002/mgg3.1960] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 12/17/2021] [Accepted: 04/18/2022] [Indexed: 12/02/2022] Open
Abstract
Background Noninvasive prenatal testing (NIPT) is a screening tool for chromosomal aneuploidies. Prior knowledge of NIPT is an inherent factor in the decision‐making process. We assessed the knowledge and attitude of pregnant women related to prenatal testing with a particular focus on NIPT. Methods A prospective cross‐sectional study, using a culturally validated questionnaire, was conducted with 342 pregnant women of whom 74.9% consented for prenatal screening. Mean age and gestational weeks ± standard deviation was 31 ± 5 and 26 ± 11, respectively. Results A positive/very positive attitude was observed to ultrasound, followed by FCT, NIPT, and lastly to CVS. More than half of the participants (56.1%) had no previous knowledge of NIPT. A reaching significance association was detected between education and knowledge of NIPT. Significant association was detected between risk for aneuploidy and knowledge of NIPT. The majority (74%) indicated their willingness to perform the test. The effect and value of society on the pregnant women to make a decision regarding NIPT was negligible. Conclusion The pregnant women in the current study displayed a lack of knowledge and awareness regarding prenatal screening, particularly the NIPT. We recommend that pregnant women receive adequate counseling regarding prenatal screening to increase their awareness and knowledge of prenatal testing, including NIPT.
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Affiliation(s)
- Maaged A. Akiel
- Department of Clinical Laboratory Sciences, College of Applied Medical SciencesKing Saud bin Abdulaziz University for Health Sciences (KSAU‐HS)RiyadhKingdom of Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC)RiyadhKingdom of Saudi Arabia
- Department of Human and Molecular GeneticsVirginia Commonwealth UniversityVirginiaUSA
| | - Mohamud S. Mohamud
- King Abdullah International Medical Research Center (KAIMRC)RiyadhKingdom of Saudi Arabia
- Research Unit, College of MedicineKing Saud bin Abdulaziz University for Health Sciences (KSAU‐HS)RiyadhKingdom of Saudi Arabia
| | - Emad M. Masuadi
- King Abdullah International Medical Research Center (KAIMRC)RiyadhKingdom of Saudi Arabia
- Research Unit, College of MedicineKing Saud bin Abdulaziz University for Health Sciences (KSAU‐HS)RiyadhKingdom of Saudi Arabia
| | - Hassan S. Alamri
- Department of Clinical Laboratory Sciences, College of Applied Medical SciencesKing Saud bin Abdulaziz University for Health Sciences (KSAU‐HS)RiyadhKingdom of Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC)RiyadhKingdom of Saudi Arabia
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Gug C, Mozos I, Ratiu A, Tudor A, Gorduza EV, Caba L, Gug M, Cojocariu C, Furau C, Furau G, Vaida MA, Stoicanescu D. Genetic Counseling and Management: The First Study to Report NIPT Findings in a Romanian Population. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58010079. [PMID: 35056387 PMCID: PMC8777823 DOI: 10.3390/medicina58010079] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/18/2021] [Accepted: 12/30/2021] [Indexed: 04/25/2023]
Abstract
Background and Objectives: Non-invasive prenatal testing (NIPT) has been confirmed as the most accurate screening test for trisomies 21, 18, 13, sex chromosomes aneuploidies and several microdeletions. This study aimed to assess the accuracy of cell free DNA testing based on low-level whole-genome sequencing to screen for these chromosomal abnormalities and to evaluate the clinical performance of NIPT. Materials and Methods: 380 consecutive cases from a single genetic center, from Western Romania were included in this retrospective study. Cell-free nucleic acid extraction from maternal blood, DNA sequencing and analysis of sequenced regions were performed by BGI Hong Kong and Invitae USA to determine the risk of specific fetal chromosomal abnormalities. In high-risk cases the results were checked by direct analysis of fetal cells obtained by invasive methods: 6 chorionic villus sampling and 10 amniocenteses followed by combinations of QF-PCR, karyotyping and aCGH. Results: NIPT results indicated low risk in 95.76% of cases and high risk in 4.23%. Seven aneuploidies and one microdeletion were confirmed, the other results were found to be a false-positive. A gestational age of up to 22 weeks had no influence on fetal fraction. There were no significant differences in fetal fraction across the high and low risk groups. Conclusions: This is the first study in Romania to report the NIPT results. The confirmation rate was higher for autosomal aneuploidies compared to sex chromosome aneuploidies and microdeletions. All cases at risk for trisomy 21 were confirmed. Only one large fetal microdeletion detected by NIPT has been confirmed. False positive NIPT results, not confirmed by invasive methods, led to the decision to continue the pregnancy. The main limitation of the study is the small number of patients included. NIPT can be used as a screening method for all pregnancies, but in high-risk cases, an invasive confirmation test was performed.
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Affiliation(s)
- Cristina Gug
- Department of Microscopic Morphology, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.G.); (D.S.)
| | - Ioana Mozos
- Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University of Medicine and Pharmacy, 300173 Timisoara, Romania
- Center for Translational Research and Systems Medicine, “Victor Babes” University of Medicine and Pharmacy, 300173 Timisoara, Romania
- Correspondence: ; Tel.: +40-745610004
| | - Adrian Ratiu
- Department of Obstetrics and Gynecology II, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Obstetrics-Gynecology Clinic IV, Municipal Emergency Clinical Hospital, 300231 Timisoara, Romania
| | - Anca Tudor
- Department of Functional Sciences, Discipline of Medical Informatics and Biostatistics, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (E.V.G.); (L.C.)
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (E.V.G.); (L.C.)
| | - Miruna Gug
- Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (M.G.); (C.C.)
| | - Catalina Cojocariu
- Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (M.G.); (C.C.)
| | - Cristian Furau
- Life Sciences Department, Faculty of Medicine, “Vasile Goldis“ Western University of Arad, 310414 Arad, Romania;
| | - Gheorghe Furau
- General Medicine Department, Faculty of Medicine, “Vasile Goldis“ Western University of Arad, 310414 Arad, Romania;
| | - Monica Adriana Vaida
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Dorina Stoicanescu
- Department of Microscopic Morphology, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.G.); (D.S.)
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Nowakowska BA, Pankiewicz K, Nowacka U, Niemiec M, Kozłowski S, Issat T. Genetic Background of Fetal Growth Restriction. Int J Mol Sci 2021; 23:ijms23010036. [PMID: 35008459 PMCID: PMC8744929 DOI: 10.3390/ijms23010036] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/14/2022] Open
Abstract
Fetal growth restriction (FGR) is one of the most formidable challenges in present-day antenatal care. Pathological fetal growth is a well-known factor of not only in utero demise in the third trimester, but also postnatal morbidity and unfavorable developmental outcomes, including long-term sequalae such as metabolic diseases, diabetic mellitus or hypertension. In this review, the authors present the current state of knowledge about the genetic disturbances responsible for FGR diagnosis, divided into fetal, placental and maternal causes (including preeclampsia), as well as their impact on prenatal diagnostics, with particular attention on chromosomal microarray (CMA) and noninvasive prenatal testing technique (NIPT).
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Affiliation(s)
- Beata Anna Nowakowska
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland;
- Correspondence: (B.A.N.); (K.P.); Tel.: +48-22-3277131 (B.A.N.); +48-22-3277044 (K.P.)
| | - Katarzyna Pankiewicz
- Department of Obstetrics and Gynecology, Institute of Mother and Child in Warsaw, Kasprzaka 17a, 01-211 Warsaw, Poland; (U.N.); (S.K.); (T.I.)
- Correspondence: (B.A.N.); (K.P.); Tel.: +48-22-3277131 (B.A.N.); +48-22-3277044 (K.P.)
| | - Urszula Nowacka
- Department of Obstetrics and Gynecology, Institute of Mother and Child in Warsaw, Kasprzaka 17a, 01-211 Warsaw, Poland; (U.N.); (S.K.); (T.I.)
| | - Magdalena Niemiec
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland;
| | - Szymon Kozłowski
- Department of Obstetrics and Gynecology, Institute of Mother and Child in Warsaw, Kasprzaka 17a, 01-211 Warsaw, Poland; (U.N.); (S.K.); (T.I.)
| | - Tadeusz Issat
- Department of Obstetrics and Gynecology, Institute of Mother and Child in Warsaw, Kasprzaka 17a, 01-211 Warsaw, Poland; (U.N.); (S.K.); (T.I.)
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Yang J, Chen M, Shen W, Wu H, Shou J, Sun J, Wu W. Knowledge, attitudes, and practices of healthcare professionals working in prenatal diagnosis toward expanded non-invasive prenatal testing in China. Prenat Diagn 2021; 42:3-14. [PMID: 34888898 DOI: 10.1002/pd.6075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 11/12/2022]
Abstract
OBJECTIVES To investigate the knowledge, attitudes, and practices of healthcare professionals (HCPs) working in prenatal diagnosis toward expanded non-invasive prenatal testing (NIPT) in China. METHODS We conducted a national online survey among HCPs working in prenatal diagnosis, including specialists in prenatal diagnosis and foetal medicine, obstetricians and gynaecologists, nurses in obstetrics and gynaecology, obstetric ultrasound doctors, and technicians in prenatal diagnosis laboratories. A total of 1882 questionnaires were collected, among which 1822 questionnaires met the research criteria and were included in the analysis. RESULTS More than 99% of all participants opted for NIPT for trisomies 21, 18, and 13. The rates of support for expanded NIPT for sex chromosome aneuploidies, rare autosomal trisomies, microdeletions and microduplications, and single-gene disorders were 93.9%, 88.6%, 89.4%, and 86.8%, respectively. Specialists in prenatal diagnosis and foetal medicine had greater knowledge but were less likely to support expanded NIPT compared to other participants. Knowledge increased with educational level, whereas support for expanded NIPT decreased with educational level. CONCLUSIONS More than 80% of HCPs working in prenatal diagnosis in China expressed support for expanding NIPT to conditions other than common trisomies. The degree of knowledge was negatively associated with the rate of support.
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Affiliation(s)
- Jing Yang
- Department of Obstetrics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Min Chen
- Department of Obstetrics and Gynecology, Department of Fetal Medicine and Prenatal Diagnosis, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wei Shen
- Department of Obstetrics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Heli Wu
- Department of Obstetrics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jian Shou
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jimei Sun
- Department of Obstetrics and Gynecology, Department of Fetal Medicine and Prenatal Diagnosis, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wenyan Wu
- BGI Guangzhou Medical Institute Company Limited, Guangzhou, Guangdong, China
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26
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Biesecker LG, Green ED, Manolio T, Solomon BD, Curtis D. Should all babies have their genome sequenced at birth? BMJ 2021; 375:n2679. [PMID: 34789511 DOI: 10.1136/bmj.n2679] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
| | - Eric D Green
- National Human Genome Research Institute, Bethesda, Maryland, USA
| | - Teri Manolio
- National Human Genome Research Institute, Bethesda, Maryland, USA
| | | | - David Curtis
- UCL Genetics Institute, University College London, UK
- Centre for Psychiatry, Queen Mary University of London, UK
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Liehr T. Non-invasive Prenatal Testing, What Patients Do Not Learn, May Be Due to Lack of Specialist Genetic Training by Gynecologists and Obstetricians? Front Genet 2021; 12:682980. [PMID: 34220958 PMCID: PMC8248176 DOI: 10.3389/fgene.2021.682980] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/27/2021] [Indexed: 11/13/2022] Open
Abstract
Platforms for "non-invasive prenatal testing" (NIPT), or also referred to as "non-invasive prenatal screening" (NIPS) have been available for over 10 years, and are the most recent tools available to obtain information about genetic condition(s) of an unborn child. The highly praised advantage of NIPT-screening is that results can provide early hints on the detection of fetal trisomies and gonosomal numerical aberrations as early as the 10th week of gestation onward, without any need for invasive procedures, such as amniocenteses or alternatives. Understandably, the public along with gynecologists and obstetricians eagerly await these early test results. Their general hope for normal (=negative) test results is also justified, as in >95% of the tested cases such an outcome is to be expected. However, pregnant women can be disappointed and confused, particularly regarding the genetic information and proposed care when the results are positive, and these emotions are also common with false-positive and false-negative NIPT results. Finally, such concerns in understanding the advantages and limitations of this routinely ordered screening tool end up at Clinical Geneticists and Genetic counselors. In this review, general background on NIPT, differences of NIPT platforms, advantages and limitations of NIPT, as well as consequences of insufficient counseling before and after NIPT are summarized. To provide comprehensive care in all pregnancies situations, professionals need a careful attitude toward offering NIPT along with specially training and qualifications in counseling for these procedures. Often it is gynecologists and obstetricians who discuss the use of NIPT with patients; however, although these physicians have a highly qualified background and knowledge in their respective specialty area(s), they may lack specific training on the interpretation of NIPT-screening results. These potential knowledge gaps must be closed quickly and comprehensively by the corresponding scientific societies to ensure optimal patient care.
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Affiliation(s)
- Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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28
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Deguchi M, Tsuji S, Katsura D, Kasahara K, Kimura F, Murakami T. Current Overview of Osteogenesis Imperfecta. ACTA ACUST UNITED AC 2021; 57:medicina57050464. [PMID: 34068551 PMCID: PMC8151368 DOI: 10.3390/medicina57050464] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/29/2021] [Accepted: 05/04/2021] [Indexed: 12/18/2022]
Abstract
Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.
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29
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Bedei I, Wolter A, Weber A, Signore F, Axt-Fliedner R. Chances and Challenges of New Genetic Screening Technologies (NIPT) in Prenatal Medicine from a Clinical Perspective: A Narrative Review. Genes (Basel) 2021; 12:501. [PMID: 33805390 PMCID: PMC8065512 DOI: 10.3390/genes12040501] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/26/2022] Open
Abstract
In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90-95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.
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Affiliation(s)
- Ivonne Bedei
- Department of Prenatal Medicine and Fetal Therapy, Justus Liebig University Giessen, 35392 Giessen, Germany; (A.W.); (R.A.-F.)
| | - Aline Wolter
- Department of Prenatal Medicine and Fetal Therapy, Justus Liebig University Giessen, 35392 Giessen, Germany; (A.W.); (R.A.-F.)
| | - Axel Weber
- Institute of Human Genetics, Justus Liebig University Giessen, 35392 Giessen, Germany;
| | - Fabrizio Signore
- Department of Obstetrics and Gynecology, Opedale S. Eugenio, 00144 Rome, Italy;
| | - Roland Axt-Fliedner
- Department of Prenatal Medicine and Fetal Therapy, Justus Liebig University Giessen, 35392 Giessen, Germany; (A.W.); (R.A.-F.)
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30
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Tan Y, Zhang L, Bai P, Li Z, Zhang R, Yang F, Wang L, Liang W. Detection of cell-free fetal DNA in maternal plasma using two types of compound markers. Electrophoresis 2021; 42:1158-1167. [PMID: 33570191 DOI: 10.1002/elps.202000318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/04/2021] [Accepted: 01/19/2021] [Indexed: 11/11/2022]
Abstract
With the discovery of circulating cell-free fetal DNA (cffDNA) in maternal plasma, noninvasive prenatal testing became possible. However, analysis of low-level cffDNA against high background maternal DNA remains complicated and challenging. To circumvent this limitation, selective amplification of cffDNA was used in this study. Two kinds of compound markers (namely DIP-STR and SNP-STR), both based on selective amplification, were used here for targeting fetal DNA. By designing two allele-specific forward primers for DIP-STR and SNP-STR, DNA fragments with different DIP/SNP alleles can be selectively amplified. When analyzing maternal plasma DNA, these markers can selectively target paternally inherited fetal alleles whose DIP/SNP allele was not shared with the mother. In this study, 21 families were studied with six DIP-STRs and 11 SNP-STRs. Fetal DNA was successfully detected across plasma samples for at least one marker. Detection rate varied between DIP-STR and SNP-STR markers, and DIP-STR outperforms SNP-STR. Fetal alleles obtained from maternal plasma were double confirmed by genotyping paternal genomic DNA and fetal genomic DNA from amniocentesis. This study demonstrated that selective amplification strategy can be used to target cffDNA in maternal plasma, which will be a promising method for noninvasive prenatal paternity testing.
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Affiliation(s)
- Yu Tan
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Sichuan, P. R. China
| | - Lin Zhang
- Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, P. R. China.,Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan, P. R. China
| | - Peng Bai
- Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, P. R. China
| | - Zhilong Li
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan, P. R. China
| | - RanRan Zhang
- Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, P. R. China
| | - Fan Yang
- Department of Ultrasonography, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Sichuan, P. R. China
| | - Li Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Sichuan, P. R. China
| | - Weibo Liang
- Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, P. R. China
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Dai R, Yu Y, Zhang H, Li L, Jiang Y, Liu R, Zhang H. Analysis of 17,428 pregnant women undergoing non-invasive prenatal testing for fetal chromosome in Northeast China. Medicine (Baltimore) 2021; 100:e24740. [PMID: 33578623 PMCID: PMC10545248 DOI: 10.1097/md.0000000000024740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 11/13/2020] [Accepted: 01/16/2021] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Non-invasive prenatal testing (NIPT) is an incomparable prenatal screening technology, but we should undergo amniocentesis to confirm fetal chromosome when pregnancies receive a positive result via NIPT. We aimed to investigate the detection rate and positive predictive value of NIPT results in pregnancies from Northeast China, and to determine the reasons for false positive and false negative NIPT results.This study evaluates 17,428 singleton pregnancies had undergone NIPT detection. 202 samples were NIPT positive with the detection rate was 1.16% (202/17,428). Among all the positive samples, 160 samples (79.21%) were referred for an amniocentesis procedure to investigate the fetal chromosome. The positive predictive value of T21, T18, and T13 was found to be 75% with a 0.07% false positive rate. Positive predictive value from high to low was as follows: trisomy 21 (84.38%), followed by trisomy 18 (61.54%), autosomal abnormalities (52.94%), sex chromosomal abnormalities (38.46%), and trisomy 13 (33.33%). The positive predictive values for sex chromosome abnormalities turned out to be mosaic sex chromosome aneuploidies (83.33%), followed by XYY (57.14%), XXY (37.50%), XXX (36.36%), and Monosomy X (28.95%). Out of the 160 samples had amniocentesis, the true positive cases in trisomy 21 had a higher percentage of Z-scores compared with the false positive cases in trisomy 21 (P < .05). And the true positive cases in trisomy 18 had a significantly higher percentage of Z-scores compared with the false positive cases in trisomy 18 (P < .01).These findings indicate that the positive predictive value of T21, T18, and T13 was found to be 75% with a 0.07% false positive rate. It is worth noting that the positive predictive value of NIPT for autosomes and sex chromosomes. Moreover, if women receive a positive result via NIPT, they should pay attention to the results with undergoing further prenatal diagnosis.
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32
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Lamy F, Ferlini A, Evangelista T. Survey on patients' organisations' knowledge and position paper on screening for inherited neuromuscular diseases in Europe. Orphanet J Rare Dis 2021; 16:75. [PMID: 33568176 PMCID: PMC7874448 DOI: 10.1186/s13023-020-01670-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 12/23/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The development of new genetic testing methods and the approval of the first treatments raises questions regarding when and how to perform screening for inherited neuromuscular conditions. Screening directives and access to the different techniques is not uniform across Europe. The patient advisory board of the European reference network for rare neuromuscular diseases (NMD) conducted a qualitative study to understand the state of play of screening for inherited NMD in Europe and patients' needs. RESULTS We collected answers from 30 patient organisations (POs) from 18 European countries. Fifteen acknowledge the existence of pre-implantation genetic diagnosis in their country. Regarding prenatal screening, we had 25 positive answers and 5 negative ones. Twenty-four POs mentioned that newborn screening was available in their country. We had some contradictory answers from POs from the same country and in some cases; diseases said to be part of the screening programmes were not hereditary disorders. Twenty-eight organisations were in favour of screening tests. The reasons for the two negative answers were lack of reimbursement and treatment, religious beliefs and eventual insurance constrains. Most POs (21) were in favour of systematic screening with the option to opt-out. Regarding the timing for screening, "at birth", was the most consensual response. The main priority to perform screening for NMDs was early access to treatment, followed by shorter time to diagnostic, preventive care and genetic counselling. CONCLUSIONS This is the first study to assess knowledge and needs of POs concerning screening for NMDs. The knowledge of POs regarding screening techniques is quite uneven. This implies that, even in communities highly motivated and knowledgeable of the conditions they advocate for, there is a need for better information. Differences in the responses to the questions "how and when to screen" shows that the screening path depends on the disease and the presence of a disease modifying treatment. The unmet need for screening inherited NMDs should follow an adaptive pathway related to the fast moving medical landscape of NMDs. International coordination leading to a common policy would certainly be a precious asset tending to harmonize the situation amongst European countries.
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Affiliation(s)
- F Lamy
- Association Française contre les Myopathies, AFM-Téléthon, Evry, France
| | - A Ferlini
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Teresinha Evangelista
- Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, 75013, Paris, France. .,AP-HP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Sorbonne Université - Inserm UMRS 974, Paris, France.
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Thomas J, Harraway J, Kirchhoffer D. Non-invasive prenatal testing: clinical utility and ethical concerns about recent advances. Med J Aust 2021; 214:168-170.e1. [PMID: 33423294 DOI: 10.5694/mja2.50928] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
| | | | - David Kirchhoffer
- Queensland Bioethics Centre, Australian Catholic University, Brisbane, QLD
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Hagstrom AD, Yuwono N, Warton K, Ford CE. Sex Bias in Cohorts Included in Sports Medicine Research. Sports Med 2021; 51:1799-1804. [PMID: 33400219 DOI: 10.1007/s40279-020-01405-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2020] [Indexed: 10/22/2022]
Affiliation(s)
- Amanda D Hagstrom
- Department of Exercise Physiology, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Nicole Yuwono
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, A/Prof Caroline Ford, Sydney, NSW, 2052, Australia
| | - Kristina Warton
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, A/Prof Caroline Ford, Sydney, NSW, 2052, Australia
| | - Caroline E Ford
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, A/Prof Caroline Ford, Sydney, NSW, 2052, Australia.
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Lledo B, Morales R, Ortiz JA, Rodriguez-Arnedo A, Ten J, Castillo JC, Bernabeu A, Llacer J, Bernabeu R. Consistent results of non-invasive PGT-A of human embryos using two different techniques for chromosomal analysis. Reprod Biomed Online 2020; 42:555-563. [PMID: 33454211 DOI: 10.1016/j.rbmo.2020.10.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/13/2020] [Accepted: 10/11/2020] [Indexed: 11/25/2022]
Abstract
RESEARCH QUESTION Are discordances in non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) results attributable to the technique used for chromosomal analysis? DESIGN A prospective blinded study was performed (September 2018 to December 2019). In total 302 chromosomal analyses were performed: 92 trophectoderm PGT-A biopsies and their corresponding spent embryo culture medium (SCM) evaluated by two methods (n = 184), negative controls (n = 8), and trophectoderm and inner cell mass biopsies from trophectoderm-aneuploid embryos (n = 18). Trophectoderm analyses were carried out using Veriseq (Illumina), and SCM was analysed using Veriseq and NICS (Yikon). RESULTS Genetic results were obtained for 96.8% of trophectoderm samples versus 92.4% for both SCM techniques. The mosaicism rate was higher for SCM regardless of the technique used: 30.4% for SCM-NICS and 28.3% for SCM-Veriseq versus 14.1% for trophectoderm biopsies (P = 0.013, P = 0.031, respectively). No significant differences in diagnostic concordance were seen between the two SCM techniques (74.6% for SCM-NICS versus 72.3% for SCM-Veriseq; P = 0.861). For embryos biopsied on day 6, these rates reached 92.0% and 86.5%, respectively. On reanalysing trophectoderm-aneuploid embryos, the discrepancies were shown to be due to maternal DNA contamination (55.6%; 5/9), embryo mosaicism (22.2%; 2/9) and low resolution in SCM-NICS (11.1%; 1/9) and in both SCM techniques (11.1%; 1/9). CONCLUSIONS This is the first study evaluating the consistency of different chromosomal analysis techniques for niPGT-A. In conclusion, the diagnostic concordance between PGT-A and niPGT-A seems independent of the technique used. Optimization of culture conditions and medium retrieval provides a potential target to improve the reliability of niPGT-A.
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Affiliation(s)
- Belen Lledo
- Molecular Biology, Instituto Bernabeu, Alicante, Spain.
| | - Ruth Morales
- Molecular Biology, Instituto Bernabeu, Alicante, Spain
| | - Jose A Ortiz
- Molecular Biology, Instituto Bernabeu, Alicante, Spain
| | | | - Jorge Ten
- Reproductive Embryology, Instituto Bernabeu, Alicante, Spain
| | | | | | - Joaquin Llacer
- Reproductive Medicine, Instituto Bernabeu, Alicante, Spain
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Jaques R, Shakeel A, Hoyle C. Novel therapeutic approaches for the management of cystic fibrosis. Multidiscip Respir Med 2020; 15:690. [PMID: 33282281 PMCID: PMC7706361 DOI: 10.4081/mrm.2020.690] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 11/06/2020] [Indexed: 12/19/2022] Open
Abstract
Cystic fibrosis (CF) is a genetic condition characterised by the build-up of thick, sticky mucus that can damage many of the body's organs. It is a life-long disease that results in a shortened life expectancy, often due to the progression of advanced lung disease. Treatment has previously targeted the downstream symptoms such as diminished mucus clearance and recurrent infection. More recently, significant advances have been made in treating the cause of the disease by targeting the faulty gene responsible. Hope for the development of potential therapies lies with ongoing research into new pharmacological agents and gene therapy. This review gives an overview of CF, and summarises the current evidence regarding the disease management and upcoming strategies aimed at treating or potentially curing this condition.
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Affiliation(s)
- Ryan Jaques
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, UK
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