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Non-invasive prenatal testing (NIPT) has the potential to screen for a wider range of genetic conditions than is currently possible at an early stage of pregnancy and with minimal risks. As such, there have been calls to apply a ‘threshold of seriousness’ to limit the scope of conditions being tested. This approach is based on concerns about society at large and the potential impact on specific groups within it. In this paper, we argue that limiting the scope of NIPT using the criterion of ‘seriousness’ is arbitrary, potentially stigmatises certain disabilities over others and fails to respect reproductive autonomy. We contend that concerns about expanded NIPT are more appropriately addressed by the provision of adequate information, counselling and consent procedures. We recommend a decision-making process that helps healthcare providers support prospective parents to make informed decisions about the nature and scope of NIPT screening based on their own values and social context. In addition to addressing concerns about expanded NIPT screening, this process would help clinicians to obtain legally valid consent and discharge their duty of care (including the duty to inform) in the prenatal context.

Background Noninvasive prenatal testing (NIPT) is commonly used to screen for fetal genetic abnormalities. However, the ability of NIPT to detect copy number variations (CNVs) has not been reported. Accordingly, in this study, we analyzed the efficiency of NIPT for the detection of fetal autosomal CNVs. Methods Patients who were positive for autosomal CNVs by NIPT and underwent diagnostic studies by karyotype analysis and chromosomal microarray (CMA) were evaluated. Samples were divided into groups according to age, in vitro fertilization, fetal‐free DNA concentration, uniquely mapped reads number, CNV size, and CNV type. Results Chromosomal microarray showed that the positive predictive value (PPV) of autosomal CNVs detected by NIPT was 14.89%. Increasing fetal DNA concentrations and uniquely mapped read numbers did not affect the PPV of CNVs detected by NIPT. There were no differences between microduplication and microdeletion PPVs detected by NIPT. The PPV of CNVs less than 10 Mb was significantly higher than that of CNVs greater than 10 Mb detected by NIPT. Conclusion The accuracy of NIPT for autosomal CNVs needs to be improved. The positive predictive value of copy number variations (CNVs) less than 10 Mb was significantly higher than that of CNVs greater than 10 Mb detected by Noninvasive prenatal testing (NIPT). NIPT was effective for detecting CNVs less than 10 Mb.

Objective To develop a technique for non‐invasive prenatal diagnosis of spinal muscular atrophy and validate its performance. Study Design Pregnant women with 1 copy of SMN1 and male fetuses were enrolled. Seventeen women were included in test set A, and 10 of them were selected into test set B randomly and blinded. The two sets were tested independently by two different researchers blinded to fetal genotypes. Fetal DNA fractions were calculated based on the relative proportion of mapped chromosome Y sequencing reads. An algorithm was developed to decide fetal SMN1 copy numbers. Results The concordance rate with the results of MLPA testing of amniocyte DNA was 94.12% in test set A and 90% in set B. For all tests with a classifiable result, the percent of agreement with the results of MLPA testing of amniocyte DNA was up to 100% (25/25). Conclusion We have developed a direct, rapid, and low‐cost technique, which has a potential to be utilized for first‐trimester non‐invasive prenatal diagnosis and screening for spinal muscular atrophy with considerable reliability and feasibility.

Background There is little evidence on the performance of non‐invasive prenatal testing (NIPT) for the detection of fetal sex chromosomal imbalances. In this review, we aimed to appraise and synthesize the literature on the performance of NIPT for the prenatal detection of fetal sex chromosome aneuploidies. Methods We performed our literature search in PubMed, Embase, Cochrane Library, Web of Science, and CADTH. Study selection and data extraction were performed by two reviewers independently. There were no restrictions on the study population. Meta‐analyses were performed with “R” software. Pooled sensitivities and specificities with their 95% CI were estimated using a random‐effects model. Heterogeneity between studies was assessed by a Q test. Results Based on 11 studies in high prior risk pregnancies, including 116 affected fetuses in aggregate, Massively Parallel Shotgun Sequencing (MPSS) had a sensitivity of 93.9% (95% CI 84.1%, 97.8%) and a specificity of 99.6% (95% CI 98.7%, 99.9%) for the detection of 45,X. Based on four studies in high‐risk pregnancies, with 83 affected fetuses in aggregate, Targeted Massively Parallel Sequencing (TMPS) had a sensitivity of 83.2% (95% CI 49.6%, 96.2%) and specificity was 99.8% (95% CI 98.3%, 100%) for the detection of 45,X. In mixed‐risk pregnancies, the sensitivity of TMPS for the detection of 45,X was 90.9% (2 studies; 95% CI 70%, 97.7%) and specificity 99.9% (2 studies; 95% CI 99.4%, 100%); MPSS data were not available in such pregnancies. Based on smaller numbers of studies, and small numbers of affected fetuses in either high‐risk or mixed‐risk pregnancies (using either MPSS or TMPS), the sensitivities and specificities were equal to or greater than 76.2% for 47,XXX, 47,XXY and 47, XYY. The test failures for SCAs were 0.2% (95% CI 0%, 13.6%) for MPSS and 5.6% (95% CI 3.7%, 8.4%) for TMPS. Conclusion High‐quality studies are still desirable in order to estimate the performance of NIPT for the detection of sex chromosome imbalances. MPSS based‐NIPT can be considered as performant for the detection of 45,X in high‐risk pregnancies, although this result is based on studies that might contain biases. For the other SCAs including 47,XXX, 47,XXY, and 47,XYY, more quality studies are still needed.

In two cases, cell‐based noninvasive prenatal testing (cbNIPT) detected pathogenic copy number variations (CNVs) in the fetal genome. cbNIPT may potentially be an improved noninvasive alternative for the detection of smaller CNVs. In two cases, cell‐based noninvasive prenatal testing (cbNIPT) detected pathogenic copy number variations (CNVs) in the fetal genome. cbNIPT may potentially be an improved noninvasive alternative for the detection of smaller CNVs

Prenatal diagnosis of hereditary diseases has substantially altered the way medical geneticists are helping families affected by genetic disorders. However, the risk of miscarriage and fear of invasive diagnostic procedures may discourage many couples from seeking prenatal diagnosis. With the discovery of maternal plasma cell-free fetal DNA, prenatal diagnosis has entered a new era of progress. Cell-free DNA is released during normal physiological functions as well as through the cell death programs of apoptosis and necrosis. It can be found in the plasma and other body fluids. Although this method has the advantage of being noninvasive, it is still rather expensive and requires advanced hardware and comprehensive data analysis. Promising implications of noninvasive prenatal diagnosis methods for the diagnosis of common trisomy disorders have paved the way for the development of more complicated assays of single-gene disorders. Relative mutation dosage and relative haplotype dosage are the most widely implemented assays for noninvasive prenatal diagnosis of single-gene disorders. However, each assay has its own advantages and disadvantages. Relative mutation dosage is based on the droplet digital polymerase chain reaction (PCR) technique which includes quantification features of real-time PCR assays. Relative haplotype dosage is based on next-generation sequencing that includes analysis of the maternal and paternal genome followed by sequencing of maternal plasma cell-free DNA. Co-amplification at a lower denaturation temperature PCR is another approach that is based on forming heteroduplexes between alleles to selectively amplify paternal mutations. In this review, we have described the most common noninvasive prenatal diagnosis approaches and compared their applications in genetic disorder diagnosis with different inheritance patterns. Key words: Cell-free nucleic acids, Prenatal diagnosis, Noninvasive prenatal testing, Single-gene diseases, Non-invasive techniques.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed.

Evidence on the diagnostic yield of genome-wide non-invasive prenatal testing (GW-NIPT) is growing, but its comparative clinical and economic impact as a first-tier screening strategy for fetal chromosomal abnormalities remains unassessed. We compared GW-NIPT with targeted NIPT and first-trimester combined testing (FCT), in a Dutch setting where all pregnancies also undergo a routine second-trimester anomaly ultrasound scan (scan), to guide policymakers on optimal prenatal screening approaches. We developed a decision-analytic model for a cohort of 175,000 pregnancies, reflecting the Dutch obstetric population. All strategies screened for common trisomies 21 (Down syndrome), 18 (Edwards syndrome), and 13 (Patau syndrome); GW-NIPT additionally considered rare autosomal trisomies and structural aberrations. Model inputs were based on the TRIDENT-2 study data and historical FCT data. Base-case unit costs were €166 (scan), €191 (FCT), and €350 (NIPT). Sensitivity analyses were conducted to account for uncertainties in model parameters and potential country-specific variations. Outcomes included total screening costs, number of fetal chromosomal abnormalities diagnosed, number of invasive procedures, and expected procedure-related euploid fetal losses. We summarized economic results as cost per diagnosed case and incremental cost per additional diagnosis across strategies. GW-NIPT yielded the highest number of diagnoses (545) versus targeted NIPT (514) and FCT (452), and the lowest cost per diagnosed case (€152,785), compared with targeted NIPT (€159,852) and FCT (€170,050). Invasive tests required per diagnosis were lower for GW-NIPT and targeted NIPT (both 6) than for FCT (13), implying a lower risk of procedure-related miscarriage (iatrogenic miscarriage). Sensitivity analyses indicated that test uptake and unit costs strongly influenced outcomes. GW-NIPT remained the most favorable in terms of cost per diagnosis for NIPT prices up to €467. Key limitations include the use of a decision-analytic model without quality-of-life outcomes and the lack of comparisons against explicit cost-effectiveness thresholds. Therefore, the results should be interpreted as relative clinical and economic comparisons rather than cost-effectiveness judgements. Among the strategies evaluated, first-tier GW-NIPT had the greatest diagnostic yield and the lowest cost per diagnosis, improving detection rates and supporting reproductive autonomy at lower costs. Implementation decisions should also consider local pricing, laboratory capacity, and counseling resources. Future research that links screening outcomes to long-term health consequences (e.g., quality-adjusted life years or life-years), healthcare utilization, costs, and psychosocial outcomes will enable formal cost-effectiveness evaluations and support further refinement of prenatal screening policy.

Fetal aneuploidies are among the most common causes of miscarriages, perinatal mortality and neurodevelopmental impairment. During the last 70 years, many efforts have been made in order to improve prenatal diagnosis and prenatal screening of these conditions. Recently, the use of cell-free fetal DNA (cff-DNA) testing has been increasingly used in different countries, representing an opportunity for non-invasive prenatal screening of pregnant women. The aim of this narrative review is to describe the state of the art and the main strengths and limitations of this test for prenatal screening of fetal aneuploidies.

Cell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy can incidentally detect maternal cancer. Additional data are needed to identify DNA-sequencing patterns and other biomarkers that can identify pregnant persons who are most likely to have cancer and to determine the best approach for follow-up. In this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.e., the fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America. We used a uniform cancer-screening protocol including rapid whole-body magnetic resonance imaging (MRI), laboratory tests, and standardized cfDNA sequencing for research purposes with the use of a genomewide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance. Cancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer. Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with nonmalignant conditions, such as fibroids. In this study, 48.6% of participants who received unusual or nonreportable clinical cfDNA-sequencing results had an occult cancer. Further study of DNA-sequencing patterns that are suggestive of occult cancer during prenatal screening is warranted. (Funded by the NIH Intramural Research Programs; ClinicalTrials.gov number, NCT04049604.).