Showing papers in "Prenatal Diagnosis in 2015"

Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis

Abstract: President President-Elect Past President Secretary Treasurer Lucas Otano MD, PhD (Argentina) Ignatia B. Van den Veyver MD (USA) Jan M.M. van Lith MD, PhD (Netherlands) Louise Wilkins-Haug MD (USA) Antoni Borrell MD, PhD (Spain) Directors Peter Benn PhD, DSc (USA) Lyn Chitty PhD (UK) Rossa Chiu (Hong Kong) Roland Devlieger MD, PhD (Belgium) Sylvie Langlois MD, CCMG (Canada) Anthony O. Odibo MD, MSCE (USA) R. Doug Wilson MD, Msc, FRCSC (Canada) Yuval Yaron MD (Israel) Diana W. Bianchi MD, ex officio (USA) Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis

Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies

Abstract: Objectives The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs-on-BeadsTM (PNBoBsTM) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBsTM under different prenatal indications. Methods A total of 9648 prenatal samples were prospectively analyzed by karyotyping plus PNBoBsTM and classified by prenatal indication. The frequencies of the genomic defects and their 95%CIs were calculated for each indication. Results The overall incidence of cryptic imbalances was 0.7%. The majority involved the DiGeorge syndrome critical region (DGS). The additional diagnostic yield of PNBoBsTM in the population with a low a priori risk was 1/298. The prevalences of DGS microdeletion and microduplication in the low-risk population were 1/992 and 1/850, respectively. Conclusions The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell-free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis. © 2015 John Wiley & Sons, Ltd.

Determination of fetal DNA fraction from the plasma of pregnant women using sequence read counts

Abstract: ObjectiveThis study introduces a novel method, referred to as SeqFF, for estimating the fetal DNA fraction in the plasma of pregnant women and to infer the underlying mechanism that allows for such statistical modeling.MethodsAutosomal regional read counts from whole-genome massively paralle

Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities

Abstract: Objective In the absence of aneuploidy or other pathogenic cytogenetic abnormality, fetuses with increased nuchal translucency (NT ≥ 3.5 mm) and/or other sonographic abnormalities have a greater incidence of genetic syndromes, but defining the underlying pathology can be challenging. Here, we investigate the value of whole exome sequencing in fetuses with sonographic abnormalities but normal microarray analysis. Method Whole exome sequencing was performed on DNA extracted from chorionic villi or amniocytes in 24 fetuses with unexplained ultrasound findings. In the first 14 cases sequencing was initially performed on fetal DNA only. For the remaining 10, the trio of fetus, mother and father was sequenced simultaneously. Results In 21% (5/24) cases, exome sequencing provided definitive diagnoses (Milroy disease, hypophosphatasia, achondrogenesis type 2, Freeman–Sheldon syndrome and Baraitser–Winter Syndrome). In a further case, a plausible diagnosis of orofaciodigital syndrome type 6 was made. In two others, a single mutation in an autosomal recessive gene was identified, but incomplete sequencing coverage precluded exclusion of the presence of a second mutation. Conclusion Whole exome sequencing improves prenatal diagnosis in euploid fetuses with abnormal ultrasound scans. In order to expedite interpretation of results, trio sequencing should be employed, but interpretation can still be compromised by incomplete coverage of relevant genes. © 2015 John Wiley & Sons, Ltd.

Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach

Abstract: Objective Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next-generation sequencing (NGS) for the analysis of cell-free DNA in maternal blood to transform prenatal diagnosis of monogenic disorders. Methods Analysis of cell-free DNA using a PCR and restriction enzyme digest (PCR–RED) was compared with a novel NGS assay in pregnancies at risk of achondroplasia and thanatophoric dysplasia. Results PCR–RED was performed in 72 cases and was correct in 88.6%, inconclusive in 7% with one false negative. NGS was performed in 47 cases and was accurate in 96.2% with no inconclusives. Both approaches were used in 27 cases, with NGS giving the correct result in the two cases inconclusive with PCR–RED. Conclusion NGS provides an accurate, flexible approach to non-invasive prenatal diagnosis of de novo and paternally inherited mutations. It is more sensitive than PCR–RED and is ideal when screening a gene with multiple potential pathogenic mutations. These findings highlight the value of NGS in the development of non-invasive prenatal diagnosis for other monogenic disorders. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Clinical outcome of subchromosomal events detected by whole‐genome noninvasive prenatal testing

Abstract: Objective A novel algorithm to identify fetal microdeletion events in maternal plasma has been developed and used in clinical laboratory-based noninvasive prenatal testing. We used this approach to identify the subchromosomal events 5pdel, 22q11del, 15qdel, 1p36del, 4pdel, 11qdel, and 8qdel in routine testing. We describe the clinical outcomes of those samples identified with these subchromosomal events. Methods Blood samples from high-risk pregnant women submitted for noninvasive prenatal testing were analyzed using low coverage whole genome massively parallel sequencing. Sequencing data were analyzed using a novel algorithm to detect trisomies and microdeletions. Results In testing 175 393 samples, 55 subchromosomal deletions were reported. The overall positive predictive value for each subchromosomal aberration ranged from 60% to 100% for cases with diagnostic and clinical follow-up information. The total false positive rate was 0.0017% for confirmed false positives results; false negative rate and sensitivity were not conclusively determined. Conclusion Noninvasive testing can be expanded into the detection of subchromosomal copy number variations, while maintaining overall high test specificity. In the current setting, our results demonstrate high positive predictive values for testing of rare subchromosomal deletions. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis.

Abstract: Objectives Chromosomal mosaicism in chorionic villi (CV) is detected in ~1–2% of cases. When a mosaic in CV is detected during prenatal diagnosis, a confirmatory karyotype should be performed on amniocytes to discriminate between a mosaic confined to the placenta [confined placental mosaicism (CPM)] and one generalized to the fetus [true fetal mosaicism (TFM)]. We determined the likelihood that any mosaic abnormalities identified through CV samples are confirmed in the fetus. Methods Over a period of 14 years, the laboratory analyzed both the cytotrophoblast and the mesenchyme of 60 347 CV samples. Cytogenetic results from CV samples showing mosaicism with follow-up amniocentesis were considered. The incidence of CPM and TFM and the risk of confirmation in the amniotic fluid (AF) were calculated. Uniparental disomy (UPD) was tested on ~300 cases at risk due to involvement of an imprinted chromosome. Results Overall, 1317 mosaic CV cases (2.18%) were detected, of which 1001 were subsequently investigated by amniocentesis. The overall risk of TFM was 13% and UPD incidence was 2.1%. Conclusions The very large presented sample set and consistency in cytogenetic methodology, especially the analysis of both placental layers performed on all CV samples will enable genetic counselors to determine the risk of fetal involvement and the clinical relevance of an identified mosaic condition. © 2015 John Wiley & Sons, Ltd.

Factors affecting levels of circulating cell-free fetal DNA in maternal plasma and their implications for noninvasive prenatal testing

Abstract: Objective Sufficient fetal DNA in a maternal plasma sample is required for accurate aneuploidy detection via noninvasive prenatal testing, thus highlighting a need to understand the factors affecting fetal fraction. Method The MaterniT21™ PLUS test uses massively parallel sequencing to analyze cell-free fetal DNA in maternal plasma and detect chromosomal abnormalities. We assess the impact of a variety of factors, both maternal and fetal, on the fetal fraction across a large number of samples processed by Sequenom Laboratories. Results The rate of increase in fetal fraction with increasing gestational age varies across the duration of the testing period and is also influenced by fetal aneuploidy status. Maternal weight trends inversely with fetal fraction, and we find no added benefit from analyzing body mass index or blood volume instead of weight. Strong correlations exist between fetal fractions from aliquots taken from the same patient at the same blood draw and also at different blood draws. Conclusion While a number of factors trend with fetal fraction across the cohort as a whole, they are not the sole determinants of fetal fraction. In this study, the variability for any one patient does not appear large enough to justify postponing testing to a later gestational age. © 2015 John Wiley & Sons, Ltd.

Overview of the impact of noninvasive prenatal testing on diagnostic procedures

Abstract: Noninvasive prenatal testing (NIPT) has had a profound influence in the field of prenatal diagnosis since the 1997 discovery of cell-free fetal DNA in maternal blood. Research has progressed rapidly, with clinical data supporting laboratory studies showing that NIPT is highly sensitive and specific for fetal aneuploidy, resulting in marked uptake in the high-risk patient population. The superior accuracy of NIPT compared with conventional screening methods has led to significant decreases in the number of invasive diagnostic procedures, in addition to a concomitant decrease in the number of procedure-related fetal losses. Yet, NIPT has been described as a 'disruptive innovation' due to the considerable changes the technology has commanded on current prenatal screening and diagnostic practices. This review summarizes both institutional and global experience with NIPT uptake, its effect on reducing diagnostic invasive procedures, and the unique challenges that reduced procedural volume may have on physician and trainee proficiency, cytogenetic laboratories, and neonatal outcome.

Global perspectives on clinical adoption of NIPT

Abstract: Objective The goals of this study were to assess global trends in clinical implementation of noninvasive prenatal testing (NIPT), as commercial tests are marketed increasingly worldwide, and to identify potential challenges for current or future use. Methods We surveyed clinicians from 46 countries about the availability of NIPT, their experiences with using NIPT, and their views on clinical, ethical, and legal issues affecting implementation in their countries. Results Forty-nine respondents from 28 countries completed the survey. The majority reported that NIPT is available in their country (n = 43) and that they offer NIPT in their current practice (n = 38). Eighteen respondents from 14 countries reported that there are plans to introduce NIPT into routine prenatal care in their country. Test prices varied widely, ranging from $350 to $2900, and several respondents observed that high test prices limited or restricted widespread use of NIPT. Responses varied both across and within countries regarding who is offered NIPT and what the overall screening protocol should be. Conclusion This study provides a snapshot of current use and experiences with NIPT globally. It also highlights differences in service provision that exists both across and within countries, emphasizing the need for developing national and international implementation guidelines for NIPT. © 2015 John Wiley & Sons, Ltd.

First trimester screening for early and late preeclampsia based on maternal characteristics, biophysical parameters, and angiogenic factors

Abstract: Objective The aim of this article is to develop the best first-trimester screening model for preeclampsia (PE) based on maternal characteristics, biophysical parameters, and angiogenic factors in a low-risk population. Methods A prospective cohort of 9462 pregnancies undergoing first-trimester screening is used. Logistic regression predictive models were developed for early and late PE (cut-off of 34 weeks' gestation at delivery). Data included the a priori risk (maternal characteristics), mean arterial pressure (MAP), and uterine artery (UtA) Doppler (11–13 weeks) in all cases. Plasma levels (8–11 weeks) of human chorionic gonadotrophin, pregnancy-associated plasma protein A, placental growth factor (PlGF), and soluble Fms-like tyrosine kinase-1 (sFlt-1) were analyzed using a nested case–control study design. Results The best model for early PE (n = 57, 0.6%) included a priori risk, MAP, UtA Doppler, PlGF, and sFlt-1 achieving detection rates of 87.7% and 91.2% for 5% and 10% false-positive rates, respectively (AUC: 0.98 [95% CI: 0.97–0.99]). For late PE (n = 246, 2.6%), the best model included the a priori risk, MAP, UtA Doppler, PlGF, and sFlt-1 achieving detection rates of 68.3% and 76.4% at 5% and 10% of false-positive rates, respectively (AUC: 0.87 [95% CI: 0.84–0.90]). Conclusion Preeclampsia can be predicted with high accuracy in general obstetric populations with a low risk for PE, by combined algorithms. Angiogenic factors substantially improved the prediction. © 2014 John Wiley & Sons, Ltd.

Clinical performance of non-invasive prenatal testing (NIPT) using targeted cell-free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies

Abstract: Objective To evaluate the clinical performance of non-invasive prenatal testing for trisomy 21, 18, and 13 using targeted cell-free DNA (cfDNA) analysis. Methods Targeted cfDNA analysis using DANSR™ and FORTE™ with microarray quantitation was used to evaluate the risk of trisomy 21, 18, and 13 in blinded samples from 799 singleton, twin, natural, and IVF pregnancies. Subjects either had fetal chromosome evaluation by karyotype, FISH, QF-PCR, or karyotype for newborns with suspected aneuploidy at birth. The results of targeted cfDNA analysis were compared to clinical genetic testing outcomes to assess clinical performance. Results Targeted cfDNA analysis with microarray quantification identified 107/108 trisomy 21 cases (99.1%), 29/30 trisomy 18 cases (96.7%), and 12/12 trisomy 13 cases (100%). The specificity was 100% for all three trisomies. Combining this data with all published clinical performance studies using DANSR/FORTE methodology for greater than 23 000 pregnancies, the sensitivity of targeted cfDNA analysis was calculated to be greater than 99% for trisomy 21, 97% for trisomy 18, and 94% for trisomy 13. Specificity for each trisomy was greater than 99.9%. Conclusion Targeted cfDNA analysis demonstrates consistently high sensitivity and extremely low false positive rates for common autosomal trisomies in pregnancy across quantitation platforms. © 2015 Ariosa Diagnostics Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies

Abstract: Objective Exome sequencing is a successful option for diagnosing individuals with previously uncharacterized genetic conditions, however little has been reported regarding its utility in a prenatal setting. The goal of this study is to describe the results from a cohort of fetuses for which exome sequencing was performed. Methods We performed a retrospective analysis of the first seven cases referred to our laboratory for exome sequencing following fetal demise or termination of pregnancy. All seven pregnancies had multiple congenital anomalies identified by level II ultrasound. Exome sequencing was performed on trios using cultured amniocytes or products of conception from the affected fetuses. Results Relevant alterations were identified in more than half of the cases (4/7). Three of the four were categorized as ‘positive’ results, and one of the four was categorized as a ‘likely positive’ result. The provided diagnoses included osteogenesis imperfecta II (COL1A2), glycogen storage disease IV (GBE1), oral–facial–digital syndrome 1 (OFD1), and RAPSN-associated fetal akinesia deformation sequence. Conclusion This data suggests that exome sequencing is likely to be a valuable diagnostic testing option for pregnancies with multiple congenital anomalies detected by prenatal ultrasound; however, additional studies with larger cohorts of affected pregnancies are necessary to confirm these findings. © 2015 John Wiley & Sons, Ltd.

Circulating cell free DNA testing: are some test failures informative?

Abstract: Objective The proportion of circulating cell free DNA derived from the feto-placental unit (fetal fraction or FF) correlates with test success and interpretation reliability. Some fetal disorders are associated with systematically lower FF, sometimes resulting in noninformative results. Methods We analyzed results from pregnancies tested in a nested case/control study derived from a cohort of 4664 high-risk pregnancies. Low FF was defined before and after adjusting for maternal weight and gestational age. Results Compared with euploid pregnancies, the median FF was significantly higher in Down syndrome pregnancies (ratio 1.17) and significantly lower in trisomy 18 and triploid pregnancies (ratios 0.71 and 0.19, respectively). Among 2157 pregnancies tested, 13 (0.6%) had FF <3.0% (all noninformative), including three trisomy 18 and three triploidy fetuses. After adjustment, 16 pregnancies (0.7%) had FF <0.3 multiples of the median (six informative), including one trisomy 18 and three triploidy fetuses. Modeled positive predictive values for low and high-risk populations were 7% and 30%, respectively. Conclusion Among women with noninformative results attributable to low FF, trisomy 18 and/or triploidy risk are sufficiently high to warrant offering additional assessments (e.g. ultrasound). If the testing indication is ultrasound abnormality, amniocentesis and karyotype/microarray should be considered. © 2014 John Wiley & Sons, Ltd.

Exome sequencing for gene discovery in lethal fetal disorders – harnessing the value of extreme phenotypes

Abstract: Massively parallel sequencing has revolutionized our understanding of Mendelian disorders, and many novel genes have been discovered to cause disease phenotypes when mutant. At the same time, next-generation sequencing approaches have enabled non-invasive prenatal testing of free fetal DNA in maternal blood. However, little attention has been paid to using whole exome and genome sequencing strategies for gene identification in fetal disorders that are lethal in utero, because they can appear to be sporadic and Mendelian inheritance may be missed. We present challenges and advantages of applying next-generation sequencing approaches to gene discovery in fetal malformation phenotypes and review recent successful discovery approaches. We discuss the implication and significance of recessive inheritance and cross-species phenotyping in fetal lethal conditions. Whole exome sequencing can be used in individual families with undiagnosed lethal congenital anomaly syndromes to discover causal mutations, provided that prior to data analysis, the fetal phenotype can be correlated to a particular developmental pathway in embryogenesis. Cross-species phenotyping allows providing further evidence for causality of discovered variants in genes involved in those extremely rare phenotypes and will increase our knowledge about normal and abnormal human developmental processes. Ultimately, families will benefit from the option of early prenatal diagnosis. © 2014 John Wiley & Sons, Ltd.

Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis.

Abstract: Objectives We aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation. Methods A next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD. Results The assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are £9025 for paternal mutation exclusion, and £26 510 for direct diagnosis. Conclusions We have developed NIPD for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

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

Abstract: 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.

Changing trends in carrier screening for genetic disease in the United States

Abstract: Genetic disease is the leading cause of infant death in the United States, accounting for approximately 20% of annual infant mortality. Advances in genomic medicine and technological platforms have made possible low cost, pan-ethnic expanded genetic screening that enables obstetric care providers to offer screening for over 100 recessive genetic diseases. However, the rapid integration of genomic medicine into routine obstetric practice has raised some concerns about the practical implementation of such testing. These changing trends in carrier screening, along with concerns and potential solutions, will be addressed. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Disparities in the Prenatal Detection of Critical Congenital Heart Disease

Abstract: Objectives Prenatal diagnosis of critical congenital heart disease, which requires surgical or catheter intervention in the first 30 days of life, allows for delivery at a specialized center and can reduce preoperative morbidity and mortality. We sought to identify the risk factors for a missed prenatal diagnosis of critical congenital heart disease. Methods Patients presenting to the Children's Hospital of Wisconsin with critical congenital heart disease from 2007 to 2013 were included. Those with a prenatal diagnosis were compared with those with a postnatal diagnosis. Results The cohort included 535 patients with prenatal diagnosis made in 326 (61%). The prenatal diagnostic rate improved from 44% in 2007 to 69% in 2013. Independent factors associated with a postnatal diagnosis were a lesion that required a view other than a four chamber view to make the diagnosis (p < 0.0001), absence of another organ system anomaly (p < 0.0001), and living in a higher poverty (p = 0.02) or lower population density communities (p = 0.002). Conclusions While the prenatal diagnostic rate for critical congenital heart disease is improving, those living in impoverished or rural communities are at highest risk of not having a diagnosis made prenatally. Interventions to improve prenatal detection of congenital heart disease should target these vulnerable areas. © 2015 John Wiley & Sons, Ltd.

The increasing incidence of foetal echogenic congenital lung malformations: an observational study.

Abstract: Objectives The aim of this study was to investigate the incidence of congenital lung malformations over the past 19 years. Congenital lung malformations (CLM) are a heterogeneous group of lung abnormalities. The antenatal diagnosis is important for foetal and neonatal management but there have been no studies examining whether the reported incidence of this abnormality is constant. Methods A retrospective cross-sectional study of cases identified from the Wessex Antenatally Detected Anomalies (WANDA) register 1994–2012. Results One hundred and thirty-three cases of CLM in 524 372 live and stillbirths were identified. All but seven were identified on antenatal ultrasound. During the early registry (1994–1998) the average incidence of CLM was 1.27 per 10 000 births. By the last 4 years (2008–2012) this had risen to 4.15 per 10 000 births, with a progressive increase during the intervening years. Conclusion There was over a three-fold increase in the antenatally detected CLM in the Wessex region 1994–2012. Comparison with the antenatal detection of diaphragmatic hernia suggests that this is a true rise in incidence rather than an artefactual increase due to increased antenatal recognition secondary to improved ultrasound resolution and operator experience. These results have clinical and cost implications for practitioners of foetal medicine, neonatology and paediatric surgery services. © 2014 John Wiley & Sons, Ltd.

The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure†

Abstract: Objectives Cell-free DNA (cfDNA) screening can provide false positive/negative results because the fetal fraction originates primarily from trophoblast. Consequently, invasive diagnostic testing is recommended to confirm a high-risk result. Currently, there is debate about the most appropriate invasive method. We sought to estimate the frequency in which a chorionic villus sampling (CVS) performed after a high-risk cfDNA result would require a follow-up amniocentesis due to placental mosaicism. Methods Analyses of the frequencies of the different types of mosaicism involving cytotrophoblasts, for trisomies 21 (T21), 18 (T18), 13 (T13) and monosomy X (MX) among 52 673 CVS karyotypes obtained from cytotrophoblast, mesenchyme and confirmatory amniocentesis. Results After a high-risk cfDNA result for T21, 18, 13 and MX, the likelihood of finding CVS mosaicism and need for amniocentesis is, respectively, 2%, 4%, 22% and 59%. When mosaicism is detected by CVS, the likelihood of fetal confirmation by amniocentesis is, respectively, 44%, 14%, 4% and 26%. Conclusions In cases of high-risk cfDNA results for T21/T18, CVS (combining cytotrophoblast and mesenchyme analysis) can be considered, but with the caveat of 2–4% risk of an inconclusive result requiring further testing. In high-risk results for MX/T13, amniocentesis would appear to be the most appropriate follow-up diagnostic test, especially in the absence of sonographic findings. © 2015 John Wiley & Sons, Ltd.

NIPT-based screening for Down syndrome and beyond: what do pregnant women think?

Abstract: Objective The aim of the study is to study pregnant women's views on noninvasive prenatal testing (NIPT) for Down syndrome and the potential to test for a broader range of conditions. Methods An online questionnaire available on the Dutch pregnancy fair website was completed by 381 pregnant women. Results Of the women, 51% expressed interest in having NIPT, including 33% of women who had declined first-trimester screening. The majority (73%) thought that the uptake of screening would increase with NIPT. Most women agreed that testing for life-threatening (89%), severe physical (79%), or severe mental (76%) disorders should be offered. A minority (29%) felt that prenatal screening should also be offered for late-onset disorders. Most (41%) preferred to have a free choice from a list of disorders, 31% preferred a ‘closed offer’, and 26% preferred choosing between packages of disorders. Although most women (76%) thought that screening for a broad range of conditions would avoid much suffering, 39% feared that it would confront couples with choices, the implications of which would be difficult to grasp. Conclusion The results suggest that the uptake of screening will increase with NIPT. If NIPT will be offered for a broad range of conditions, it is crucial to find a way that facilitates rather than undermines well-informed decision-making. © 2015 John Wiley & Sons, Ltd.

Nationwide demonstration project of next-generation sequencing of cell-free DNA in maternal plasma in Japan: 1-year experience

Abstract: Objective To report the 1-year experience of a nationwide demonstration project to introduce noninvasive prenatal testing of aneuploidy from maternal plasma and discuss how to implement this program in Japan. Methods The test was conducted to detect aneuploidy in high-risk pregnant women with adequate genetic counseling. The clinical data, test results, and pregnancy outcomes were recorded. Results Of the 7740 women tested, 142 (1.8%) had positive results, 7594 (98.1%) had negative results, and four (0.1%) had results that were not reportable. Of the 142 women who tested positive, 13 cases resulted in intrauterine fetal death, and three cases refused to undergo the invasive procedure. Of the 126 positive cases confirmed on karyotyping, a normal karyotype was observed for trisomy 21 in three cases, trisomy 18 in eight cases, and trisomy 13 in two cases. In the follow-up study of the negative cases (n = 1638), only one false-negative case of trisomy 18 was detected. Conclusions We described our nationwide 1-year experience with noninvasive prenatal genetic testing. It is expected that the present data will stimulate a debate regarding prenatal genetic testing and hopefully lead to improvements in the perinatal care system with respect to genetic counseling in Japan. © 2014 John Wiley & Sons, Ltd.

Perinatal outcome after maternal primary cytomegalovirus infection in the first trimester: a practical update and counseling aid.

Abstract: Cytomegalovirus (CMV) is the most common cause of congenital infection with approximately 05% of pregnant women in developed countries seroconverting during pregnancy In utero transmission occurs in about one third of women who develop primary infection in the first trimester, and these fetuses are at risk for adverse perinatal outcomes and long-term neurological complications The great promise of a prenatal therapy to reduce fetal infection after maternal primary CMV infection has not been realized to date The prediction of CMV sequelae is particularly challenging for clinicians because of the heterogeneity of the published literature, the wide spectrum of perinatal outcomes, the adjustment of fetal risk at each stage of assessment, and the variable quality of published data Given the continued lack of a proven fetal therapy, it is timely to review the natural history of congenital CMV in the modern management era We have analyzed the recent literature, integrated findings from multiple studies, and calculated stage-specific risks for adverse perinatal outcome to assist in counseling women with first trimester primary CMV infection

Prenatal whole-exome sequencing: parental attitudes.

Abstract: Objective The aim of this study was to survey the opinions of expectant parents regarding prenatal whole-exome sequencing. Methods The study used a questionnaire that focused on acceptability of prenatal whole-exome sequencing to individuals who pursued first-trimester prenatal screening in a tertiary academic medical center. A total of 186 expectant individuals completed the questionnaire. The results of the questionnaire were analyzed using descriptive statistics and logistic regression models. Results Eighty-three percent of the participants answered that prenatal whole-exome sequencing should be offered, 14.8% were neutral, and only 2.2% disagreed. Fifty-four percent of the participants were interested in having prenatal whole-exome sequencing for their fetus, 40.1% were neutral, and 6.6% disagreed. The majority of participants expressed a desire to know about treatable (96.2%) and non-treatable (86.3%) childhood conditions, and most said the same for treatable (76.0%) and non-treatable (74.3%) adult-onset conditions. Over half of the participants (59.7%) indicated a maximum acceptable turnaround time of 3 weeks or less for prenatal whole-exome sequencing. Conclusions The majority of respondents felt prenatal whole-exome sequencing should be offered. Moreover, the majority wanted to know prenatally about treatable and non-treatable childhood and adult conditions. © 2015 John Wiley & Sons, Ltd.

Computer-assisted surgical planning and intraoperative guidance in fetal surgery: a systematic review†

Abstract: Fetal surgery has become a clinical reality, with interventions for twin‐to‐twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance. We introduce the concept of computer‐assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology. Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal‐specific technology in order to improve fetal surgical outcome. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

The influence of low molecular weight heparin medication on plasma DNA in pregnant women.

Abstract: LifeCodexx AG, Constance, Germany BioGen Medical Instruments Co. Ltd., Istanbul, Turkey GATC Biotech AG, Constance, Germany Praxis für Pränatalmedizin und Humangenetik, Münster, Germany Praxisgemeinschaft am Goetheplatz, Frankfurt am Main, Germany Institut für Praenatale Medizin & Humangenetik, Wuppertal, Germany Zentrum für Pränataldiagnostik und Humangenetik, Berlin, Germany Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany *Correspondence to: Wera Hofmann. E-mail: w.hofmann@lifecodexx.com Late-breaking abstract presentation during the plenary session at the ISPD conference, Tuesday, 14 July 2015.

Cell-free DNA screening and sex chromosome aneuploidies.

Abstract: Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal aneuploidies. This technology may also identify fetal sex and can be used to screen for sex chromosome aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal sex is also discussed.

Non-invasive prenatal diagnostic testing for β-thalassaemia using cell-free fetal DNA and next generation sequencing.

Abstract: Objective To develop an accurate non-invasive prenatal test using next generation sequencing (NGS) for HbE and the four most common β-thalassaemia mutations found in South East Asia (namely −28A > G, CD17A > T, CD41/42(−TTCT) and IVS-II-654C > T). Methods Cell-free DNA was extracted from maternal plasma from 83 families where both parents were carriers of the HbE mutation or one of four common β-thalassaemia mutations. Overlapping PCR amplicons covering each mutation were generated, pooled and sequenced using the Illumina MiSeq. Fastq files were analysed to detect inheritance of the paternal mutation. Results In two cases where the fathers were compound heterozygotes for HbE and −28A > G, the fetus was correctly diagnosed as having inherited one of the paternal mutations. In 35/85 cases, the paternal mutation was not detected, and in 50/85 cases, it was classified as inherited. Overall sensitivity for detection of paternal mutations was 100% (95% CI: 92.4–100%), and specificity was 92.1% (95% CI: 79.2–97.3%). Conclusion We demonstrated that detection of paternal mutations using NGS can be readily achieved with high sensitivity and specificity, removing the need for an invasive test in 50% of pregnancies at risk of a thalassaemia in cases where the father and mother carry a different mutation. © 2014 John Wiley & Sons, Ltd.

Reproductive genetic counseling challenges associated with diagnostic exome sequencing in a large academic private reproductive genetic counseling practice

Abstract: Objective Diagnostic whole exome sequencing (WES) is rapidly entering clinical genetics, but experience with reproductive genetic counseling aspects is limited. The purpose of this study was to retrospectively review and report on our experience with preconception and prenatal genetic counseling for diagnostic WES. Method We performed a retrospective chart review over 34 months in a large private prenatal genetic counseling practice and analyzed data for referral indications, findings, and results of genetic counseling related to diagnostic WES. Results Ten of 14 patients counseled about diagnostic WES for ongoing pregnancies pursued the test, resulting in identification of three pathogenic variants (30%). Five of 15 patients seeking counseling about familial WES results in an affected proband pursued prenatal diagnosis, resulting in identification of one affected fetus and five unaffected fetuses. We experienced challenges related to complexity and uncertainty of results, turnaround time, cost and insurance overage, and multidisciplinary fetal care coordination. Conclusion Despite having experienced complexity and identified challenges of the reproductive genetic counseling, availability of diagnostic WES contributed important information that aided in prenatal care planning and decision-making. Future enhanced provider education and larger studies to systematically study the integration of WES in reproductive genetic counseling and prenatal care will be important. © 2015 John Wiley & Sons, Ltd.