Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

Objective

There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

Method

We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics.

Results

Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers.

Conclusion

Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.     

Prenatal genetic counselling for psychiatric disorders

Psychiatric disorders like schizophrenia, bipolar disorder, depression, anxiety, and obsessive–compulsive disorder are common disorders with complex aetiology. They can exact a heavy toll on the individual with the condition and can have significant impact on family members too. Accordingly, psychiatric disorders can arise as a concern in the prenatal context – couples may be interested in learning about the chance for their child to develop the illness that manifests in the family and may be interested in discussing options for prenatal testing. However, the complex nature of these conditions can present challenges for clinicians who seek to help families with these issues. We established the world's first specialist genetic counselling service of its kind in Vancouver, Canada, in 2012, and to date, have provided counselling for ~500 families and have demonstrated increases in patients' empowerment and self efficacy after genetic counselling. We draw on our accumulated clinical experience to outline the process by which we approach prenatal genetic counselling for psychiatric disorders to assist other clinicians in providing thoughtful, comprehensive support to couples seeking out this service. © 2016 John Wiley & Sons, Ltd.     

基于读者反应的红色旅游英译文本可读性研究

随着我国红色旅游业的快速发展,以翻译为主要途径的外宣工作的重要性日益彰显,如何评价外宣文本的可读性逐渐成为学界关注的热点问题。文中以井冈山景区的英译文本为例,通过问卷调查和访谈的方式收集了十五位目标语读者关于外宣文本的反馈意见。结果显示:译文的可读性受文本质量、文本长度和读者背景等诸多因素的影响。由于译者对英译文本的目标语读者和文本功能认识不足,译文在词汇、语句和语篇等层面均存在不同程度的问题。     

Prenatal ultrasound finding of atypical genitalia: Counseling,genetic testing and outcomes

Objective

To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies.

Methods

A retrospective cohort study (2017–2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US.

Results

In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1.

Conclusions

For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.     

Reproductive behaviour and prenatal diagnosis following genetic termination of pregnancy in women of advanced maternal age

One hundred and fifty-one women of advanced maternal age who underwent genetic termination of pregnancy (TOP) were studied for their reproductive behaviour and the type of procedure for prenatal diagnosis in a subsequent pregnancy. A total of 59 women (39 per cent) had a further pregnancy. In all continuing pregnancies prenatal diagnosis was performed, of which 75 per cent consisted of chorionic villus sampling (CVS). Reproductive behaviour following a genetic termination was negatively correlated with maternal age and parity. Both reproductive behaviour and the choice to undergo a diagnostic procedure in the next pregnancy were independent of the type of diagnostic procedure in the previous affected pregnancy.     

Recommended pre-test counseling points for noninvasive prenatal testing using cell-free DNA: a 2015 perspective

Noninvasive prenatal testing (NIPT) using cell-free DNA is being offered to an increasing number of women. Comprehensive pre-test counseling is complicated by emerging information about the benefits and limitations of testing, as well as the potential to detect incidental findings. Genetic counselors are trained to facilitate informed decision-making; however, not all centers have access to these professionals. To aid in the informed consent process, we have summarized key points to be included in discussions with patients who are considering NIPT. © 2015 John Wiley & Sons, Ltd.     

Reasons for women's non-uptake of amniocentesis

More than 10 years after a chromosomal anomaly screening programme was set up in France for pregnant women of advanced age, amniocentesis is still a controversial issue. The reasons why eligible women did not utilize the test and whether or not the existence of social welfare coverage determined women's access to prenatal diagnosis were studied. A group of 291 women aged ⩾35 years who recently gave birth to normal liveborns was interviewed by telephone. Among those aged 38 years and over, who automatically qualified for social security coverage, 75 per cent had undergone amniocentesis as opposed to 23 per cent in the 35 to 37-year-old non-covered age group who did not qualify for social security coverage. In both groups, access to amniocentesis was found to depend on the physicians', women's and male partners' attitudes towards prenatal diagnosis and abortion. Among the younger group, the uptake depended mainly on socio-economic factors. Institutional policies should ensure greater equality of access while allowing for individual preferences.     

Prenatal diagnosis of sex chromosome aneuploidy: possible reasons for high rates of pregnancy termination

Sex chromosome aneuploidy (SCA), when detected in amniocentesis, is usually an unexpected result of a test carried out for another purpose. For most SCAs, the prognosis is milder and less predictable than trisomy 21, and therefore parents are faced with a difficult decision regarding the option of pregnancy termination. While studies from Europe and the USA report a declining trend in termination rates for SCA, our local experience is different. During the period 1989–1998, we diagnosed 60 SCA (including mosaics) in 20 106 amniocenteses (0.29%) and 48 (80%) of these pregnancies were terminated, a significantly higher proportion than has been reported in Europe and the USA. The present study shows that the difference between our experience and others' may be related to differences in cultural norms and values. Thirty women were interviewed, of whom 23 terminated and seven continued the pregnancy. Interview analyses showed that the main reason behind the decision to terminate the pregnancy was associated with the parents' fear of non-specific abnormality of the child, and concerns about abnormal sexual development. Although genetic counseling practised in our center aims to be non-directive, 56% of the women reported that the counseling was either directive towards termination, or that they at least felt that the counselor's attitude was pro-termination. Most women (93%) reported themselves as having come to terms with their decision. Copyright © 2001 John Wiley & Sons, Ltd.     

The role of prenatal diagnosis following preimplantation genetic testing for single-gene conditions: A historical overview of evolving technologies and clinical practice

Preimplantation genetic testing for monogenic conditions (PGT-M) has become a valued reproductive option for couples at risk of having a child with a single gene condition. In line with developments in molecular genetics, there has been an overall trend toward laboratory techniques with higher accuracy in comparison to earlier PGT-M techniques. The recommendation for confirmatory prenatal diagnostic testing has remained a standard component of PGT-M counseling, reflecting the inherent difficulties of testing the limited number of cells obtained from embryo biopsy, as well as recognition of the biological and human factors that may lead to misdiagnosis in a PGT-M cycle. Reported misdiagnosis rates are less than 1 in 200 pregnancies following PGT-M, although updated data regarding newer methods of PGT-M are required. There is limited evidence available regarding clinician and patient behavior in pregnancies resulting from PGT-M cycles. It remains essential that clinicians involved in the care of patients undergoing PGT-M provide appropriate counseling regarding the risks of misdiagnosis and the importance of confirmatory prenatal diagnosis. The nature of PGT-M test design lends itself to cell-free DNA-based noninvasive prenatal testing for monogenic conditions (NIPT-M), which is likely to become a popular method in the near future.     

Commercial landscape of noninvasive prenatal testing in the United States

Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times, and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers, and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests. © 2013 John Wiley & Sons, Ltd.     

Genetic counselling and ethical issues with chromosome microarray analysis in prenatal testing

Molecular karyotyping using chromosome microarray analysis (CMA) detects more pathogenic chromosomal anomalies than classical karyotyping, making CMA likely to become a first tier test for prenatal diagnosis. Detecting copy number variants of uncertain clinical significance raises ethical considerations. We consider the risk of harm to a woman or her fetus following the detection of a copy number variant of uncertain significance, whether it is ethically justifiable to withhold any test result information from a woman, what constitutes an ‘informed choice’ when women are offered CMA in pregnancy and whether clinicians are morally responsible for ‘unnecessary’ termination of pregnancy. Although we are cognisant of the distress associated with uncertain prenatal results, we argue in favour of the autonomy of women and their right to information from genome-wide CMA in order to make informed choices about their pregnancies. We propose that information material to a woman's decision-making process, including uncertain information, should not be withheld, and that it would be paternalistic for clinicians to try to take responsibility for women's decisions to terminate pregnancies. Non-directive pre-test and post-test genetic counselling is central to the delivery of these ethical objectives. © 2012 John Wiley & Sons, Ltd.     

New genetic and clinical evidence associated with fetal Beckwith–Wiedemann syndrome

Early detection of Beckwith–Wiedemann syndrome (BWS) is very important since it is very useful regarding counseling of parents concerning the risk of developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, prevention of neonatal hypoglycemia and even options of pregnancy termination in non-viable fetuses. This report describes the prenatal classic sonographic triad of fetal BWS (omphalocele, macrosomia, macroglossia) and other supporting findings (hepatomegaly, adrenal enlargement) as well as additional postnatal evidence. Also, it demonstrates new molecular genetic evidence potentially associated with the disease (the presence of a novel heterozygous c.358G>T variant of the CDKN1C gene). Importantly, we provide new evidence indicating that elevated levels of the four serum biomarkers (alpha-fetoprotein, beta-human gonadotropin, unconjugated estriol, and inhibin-A) in late first or early second trimester might be strongly suggestive of BWS which may facilitate early detection especially in cases of no obvious anomaly. In conclusion, this study emphasizes on early detection of BWS as early as at 14 weeks of gestation, based on the abnormal rise of the four serum biomarkers together with omphalocele. To the best of our knowledge, this is the earliest prenatal detection of BWS ever reported. Finally, we provide new molecular genetic evidence that is, potentially associated with BWS.     

Maternity health care professionals' views and experiences of fetal genomic uncertainty: A review

The field of prenatal screening and diagnosis for fetal anomalies has been marked by a rapid succession of technological advances, including most notably, chromosomal microarray analysis, and next generation sequencing. Despite the diagnostic advantages of these technologies, their incorporation into prenatal testing has created additional challenges of revealing genomic variants of unknown or uncertain significance, and secondary findings. While detailed posttest counseling about uncertain variants is best performed by medical geneticists, many of the screening and diagnostic tests that lead to this information are actually ordered by general maternity health care professionals (HCPs), such as obstetricians, midwives, and family physicians. Maternity HCPs support pregnant women through to the conclusion of their pregnancy and the postpartum period, and thus are close observers of the psychosocial impart of fetal genomic uncertainty on women and their families. While there have been many studies exploring the handling of genomic uncertainty by genetics HCPs, there has been relatively less attention paid to maternity HCPs without speciality training in genetics. This review explores the current literature surrounding nongenetic maternity HCPs' views and experiences of genomic uncertainty and returning uncertain results in the prenatal setting.     

Rapid prenatal diagnosis of Facioscapulohumeral Muscular Dystrophy 1 by combined Bionano optical mapping and karyomapping

Purpose

To explore the feasibility of performing rapid prenatal diagnoses of FSHD1 using a combination of Bianano optical mapping and linkage-based karyomapping.

Methods

DNA specimens from a family that had been previously diagnosed with FSHD1 using Southern Blot analysis were used for this study. Genetic diagnosis of the proband, fetus chorionic amniotic fluid, and aborted fetal tissue was performed using Bianano optical mapping (BOM) together with linkage-based karyomapping.

Results

BOM analysis showed that the proband's 4q35.2 region contained four D4Z4 repeats and the 4qA permissible allele, consistent with the previous FSHD1 diagnosis obtained by Southern Blotting. BOM analysis of the fetus' 4q35.2 region was consistent with that of the proband. Karyomap analysis revealed that the fetus inherited the affected chromosome segment from the proband. After genetic counseling, the couple choose termination of pregnancy, and we performed gene diagnosis of the abortus tissue by BOM.

Conclusions

Bianano optical mapping can determine the number of D4Z4 repeats and exclude interference of the 10q26.3 homologous region, and in combination with karyomapping, can be used for rapid and accurate prenatal diagnosis of FSHD1.     

Physicians' acceptability of termination of pregnancy after prenatal diagnosis in southern france

The acceptability of prenatal diagnosis for Down's syndrome has been extensively studied over the last 15 years but that of other pathologies remains largely unexplored. The main goals of this study were to approach physicians' opinions on six reasons for termination of pregnancy showing different deficiencies, i.e., Down's, Turner and Klinefelter syndromes, cystic fibrosis, spina bifida, and haemophilia, and to identify the origins of reserves. The influence of sociodemographic and professional characteristics of physicians on their opinions and attitudes during the consultation were studied. The data presented are based on information gathered in 1985 by a mailed questionnaire answered by 853 general practitioners, gynaecologists, obstetricians, and pediatricians in the Marseilles Genetic Centre's region. Stepwise logistic regression was used for the multivariate analysis. The results showed that 78 per cent of those answering favour termination of pregnancy for Down's syndrome and that only moral reticences were mentioned by the physicians opposed. Conversely, for haemophilia, only 21 per cent of the physicians considered this indication justified; those opposed were for the most part concerned that severity of illness did not justify termination of pregnancy. Overall, 33 per cent of physicians would voice their personal opinion on termination of pregnancy if so requested by consultees. Results on the influence of age and specialty evidenced their role on physicians' opinions. Indeed, 30 per cent of physicians opposed to pregnancy termination for one of the six fetal anomalies retained herein would modify their positions if diagnosis were possible in the first trimester of pregnancy.     

Antenatal gene tests in low-risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland

Approximately one in five subjects in Finland carries some gene defect associated with 30 diseases belonging to the Finnish disease heritage, and about one in 500 children born is affected. Almost all carriers, women and men, are unaware of their condition. Recent advances in molecular medicine have offered the possibility of population-based carrier screening for recessive disorders. We studied acceptance and attitudes to antenatal screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL). From January 1995 until December 1996 carrier tests were offered at Kuopio City Health Center, free of charge to all pregnant women attending maternity care units. Women found to be carriers of AGU (n=47) or INCL (n=14) underwent detailed genetic counseling, and their male partners were also offered the test. If both partners appeared to be carriers we offered prenatal testing (n=1). No affected fetuses were detected. Attitudes towards the gene test were elicited by means of a questionnaire. Altogether 87% of pregnant women elected to undertake the gene tests. Antenatal screening for gene defects was feasible and well accepted, and it provided an effective way to find carriers of genetic diseases and to incorporate prenatal testing into this process. Copyright © 2001 John Wiley & Sons, Ltd.     

Towards informed decisions about prenatal testing: A review

There are now several well-documented psychological problems associated with prenatal testing programmes. These include poor understanding of tests undergone or declined, anxiety following false positive results, and false reassurance in those receiving negative test results. There is, as yet, little evidence concerning how to provide services to circumvent these. The focus of this review is upon just one of these problems: how best to inform women about prenatal testing and their reproductive options following the diagnosis of a fetal abnormality. Possible methods of improving informed decision-making either about whether to undergo testing or whether to terminate an affected pregnancy are described drawing upon research from antenatal and other health care areas. Future challenges for clinical practice and research in this area concern the range of conditions and predispositions for which prenatal testing with the option of termination should be offered.     

Preimplantation genetic diagnosis at 20 years

First reported in 1990, PGD has evolved into a complementary form of prenatal diagnosis offering novel indications. DNA for PGD can be recovered with equal safety and facility from polar bodies I and II, blastomere (8 cell embryo) and trophectoderm (5–6 day blastocyst). Diagnostic accuracy is very high (>99%) for both chromosomal abnormalities and single gene disorders. Traditional application of FISH with chromosome specific probes for detecting aneuploidy and translocations may be replaced or complemented by array comparative genome hybridization (array CGH); biopsied embryos can now be cryopreserved (vitrification) while analysis proceeds in orderly fashion. PGD has been accomplished for over 200 different single gene disorders. Novel indications for PGD not readily applicable by traditional prenatal genetic diagnosis include avoiding clinical pregnancy termination, performing preconceptional diagnosis (polar body I), obtaining prenatal diagnosis without disclosure of prenatal genotype (nondisclosure), diagnosing adult-onset disorders particularly cancer, and identifying HLA compatible embryos suitable for recovering umbilical cord blood stem cells. Copyright © 2010 John Wiley & Sons, Ltd.     

Prenatal diagnosis of charcot-marie-tooth disease type 1a (CMT1A) using molecular genetic techniques

Charcot-Marie-Tooth disease type 1A (CMT1A) is a frequent hereditary motor and sensory neuropathy of the peripheral nerves. In most cases, the disease is associated with a 1.5 Mb tandem duplication at 17p11.2. A 42-year-old pregnant woman requested prenatal diagnosis because of her age and since both her husband and two children were severely affected with CMT1. The CMT1A duplication was demonstrated in the father's, the two children's, and the fetus's DNA using different molecular genetic methods. Although cytogenetical analysis showed a normal female karyotype in the fetus, the parents decided to terminate the pregnancy because of the genetic risk associated with the CMT1A duplication.