Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population.MethodsMedline (PubMed) and Embase were used to identify studies examining detection of Down syndrome (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies, rare autosomal trisomies, copy number variants, and maternal conditions, as well as studies assessing the psychological impact of NIPS and the rate of subsequent diagnostic testing. Random-effects meta-analyses were used to calculate pooled estimates of NIPS performance (P < .05). Heterogeneity was investigated through subgroup analyses. Risk of bias was assessed.ResultsA total of 87 studies met inclusion criteria. Diagnostic odds ratios were significant (P < .0001) for T21, T18, and T13 for singleton and twin pregnancies. NIPS was accurate (≥99.78%) in detecting sex chromosome aneuploidies. Performance for rare autosomal trisomies and copy number variants was variable. Use of NIPS reduced diagnostic tests by 31% to 79%. Conclusions regarding psychosocial outcomes could not be drawn owing to lack of data. Identification of maternal conditions was rare.ConclusionNIPS is a highly accurate screening method for T21, T18, and T13 in both singleton and twin pregnancies.     

DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study

PurposePrenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement.MethodsA blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory.ResultsDown syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance.ConclusionWhen applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.     

DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study

PurposeTo determine whether maternal plasma cell–free DNA sequencing can effectively identify trisomy 18 and 13.MethodsSixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias.ResultsAmong the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset.ConclusionAmong high-risk pregnancies, sequencing circulating cell–free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.Genet Med 2012:14(3):296–305     

Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions

PurposeThe purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening.MethodsAn unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies.ResultsOverall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected.ConclusionAlthough traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (～10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.     

Prenatal cell-free DNA screening test failures: a systematic review of failure rates,risks of Down syndrome,and impact of repeat testing

PurposeWe systematically reviewed the published literature on test failure rates for the sequencing of cell-free DNA (cfDNA) in maternal plasma to identify Down syndrome.MethodsWe searched peer-reviewed English publications with diagnostic results on all pregnancies that provided test failure rates. Data on the odds of failure in Down syndrome and euploid pregnancies and the impact of repeat testing were extracted. Random-effects modeling was then used to identify moderators that could explain variability.ResultsThirty articles satisfied the inclusion criteria for overall failure rates. Study location (Western and Asian with initial testing, and Western with repeat testing) were significant moderators with failure rates of 3.3, 0.6, and 1.2%, respectively (P = 0.001). The odds ratio for Down syndrome in successful versus failed tests was 0.98 (95% confidence interval: 0.62–1.55, I² = 0%). Repeat testing from 14 large clinical cohort studies found that 83% (range: 52–100%) of failures were repeated, with 79% (range: 46–97%) being successful.ConclusionLower failure rates in Asian studies may be related to not routinely measuring the fetal fraction and to fewer obese women. Repeat cfDNA testing is effective in providing reliable results after initial failures. Protocols for primary cfDNA screening should focus on Down syndrome, with less common and more structurally abnormal trisomy 18 and 13 pregnancies treated as adjuncts.     

Chromosomal microarray vs. NIPS: analysis of 5541 low-risk pregnancies

PurposeTo evaluate the diagnostic yield of chromosomal microarray (CMA) in pregnancies with normal ultrasound.MethodsThis retrospective cohort analysis included all pregnancies with normal ultrasound undergoing CMA testing between the years 2010 and 2016. We calculated the rate of detection of clinically significant CMA findings in the whole cohort and according to various indications.ResultsOf 5541 CMA analyses, clinically significant findings were yielded in 78 cases (1.4%). Of these, 31 (39.7%) variants could have theoretically been detected by karyotyping (e.g., sized above 10 Mb), and 28 (35.9%) by noninvasive prenatal screening aimed at five common aneuploidies. Of the 47 submicroscopic findings detectable by CMA only, the majority (37 cases, 78.7%) represented known recurrent syndromes. Detection of clinically significant CMA findings in women with no indication for invasive testing was 0.76% (21/2752), which was significantly lower compared with 1.8% in advanced maternal age group (41/2336), 2.8% in abnormal biochemical serum screening (6/211), and 4.1% (10/242) in fetuses with sonographic soft markers.ConclusionClinically significant CMA aberrations are detected in 1 of 71 pregnancies with normal ultrasound, and in 1 of 131 women with no indication for invasive testing. Thus, CMA might be recommended a first-tier test in pregnancies with normal ultrasound.     

Clinical utility of noninvasive prenatal screening for expanded chromosome disease syndromes

PurposeTo assess the clinical performance of an expanded noninvasive prenatal screening (NIPS) test (“NIPS-Plus”) for detection of both aneuploidy and genome-wide microdeletion/microduplication syndromes (MMS).MethodsA total of 94,085 women with a singleton pregnancy were prospectively enrolled in the study. The cell-free plasma DNA was directly sequenced without intermediate amplification and fetal abnormalities identified using an improved copy-number variation (CNV) calling algorithm.ResultsA total of 1128 pregnancies (1.2%) were scored positive for clinically significant fetal chromosome abnormalities. This comprised 965 aneuploidies (1.026%) and 163 (0.174%) MMS. From follow-up tests, the positive predictive values (PPVs) for T21, T18, T13, rare trisomies, and sex chromosome aneuploidies were calculated as 95%, 82%, 46%, 29%, and 47%, respectively. For known MMS (n = 32), PPVs were 93% (DiGeorge), 68% (22q11.22 microduplication), 75% (Prader–Willi/Angleman), and 50% (Cri du Chat). For the remaining genome-wide MMS (n = 88), combined PPVs were 32% (CNVs ≥10 Mb) and 19% (CNVs <10 Mb).ConclusionNIPS-Plus yielded high PPVs for common aneuploidies and DiGeorge syndrome, and moderate PPVs for other MMS. Our results present compelling evidence that NIPS-Plus can be used as a first-tier pregnancy screening method to improve detection rates of clinically significant fetal chromosome abnormalities.     

A quantitative cSMART assay for noninvasive prenatal screening of autosomal recessive nonsyndromic hearing loss caused by GJB2 and SLC26A4 mutations

PurposeThe aim of this study was to assess the performance of a noninvasive prenatal screening (NIPS) assay for accurate fetal genotyping of pregnancies at genetic risk for autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsA total of 80 pregnant couples carrying known mutations in either the GJB2 or SLC26A4 genes associated with a risk for ARNSHL were recruited to the study. Fetal amniocyte samples were genotyped by invasive prenatal screening (IPS), whereas the cell-free fetal DNA present in maternal plasma samples was genotyped using a novel NIPS method based on circulating single-molecule amplification and resequencing technology (cSMART).ResultsIPS of the 80 at-risk pregnancies identified 20 normal homozygote, 42 heterozygote, 5 affected homozygote, and 13 affected compound heterozygote fetuses. Benchmarking against IPS, 73 of 80 fetuses (91.3%) were correctly genotyped by the cSMART NIPS assay. A low fetal DNA fraction (<6%) was identified as the main contributing factor in five of seven discordant NIPS results. At fetal DNA fractions >6%, the sensitivity and specificity of the cSMART assay for correctly diagnosing ARNSHL were 100 and 96.5%, respectively.ConclusionBased on key performance indicators, the cSMART NIPS assay has clinical potential as an alternative to traditional IPS of ARNSHL.     

Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: results of the TRIDENT study

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (<p10), which was severe (<p2.3) in six cases.ConclusionGenome-wide NIPS in pregnancies at risk for trisomy 21, 18, or 13, reveals a chromosomal aberration other than trisomy 21, 18 or 13 in about one-third of the abnormal cases. The majority involves a fetal or placental chromosome aberration with clinical relevance for pregnancy management.     

Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases

PurposeInvasive diagnostic prenatal testing can provide the most comprehensive information about the genetic status of a fetus. Noninvasive prenatal screening methods, especially when using cell-free DNA (cfDNA), are often limited to reporting only on trisomies 21, 18, and 13 and sex chromosome aneuploidies. This can leave a significant number of chromosomal and subchromosomal copy-number variations undetected. In 2015, we launched a new genome-wide cfDNA screening test that has the potential to narrow this detection gap.MethodsHere, we review the results from the first 10,000 cases submitted to the Sequenom clinical laboratory for genome-wide cfDNA screening.ResultsThe high-risk indication for this cohort differed compared with standard cfDNA screening. More samples were submitted with ultrasound indications (25% compared with 13% for standard cfDNA screening) and fewer for advanced maternal age (51% for genome-wide screening versus 68% for standard cfDNA screening). A total of 554 positive calls were made, of which 164 were detectable only via genome-wide analysis.ConclusionThis reports indicates a difference in utilization compared with standard cfDNA screening, where positivity rates are higher and a large subset of positive calls could not have been made using standard cfDNA screening.     

Outcome of publicly funded nationwide first-tier noninvasive prenatal screening

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation.MethodsThe performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered.ResultsTrisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%.ConclusionExpanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.     

Cell-free fetal DNA versus maternal serum screening for trisomy 21 in pregnant women with and without assisted reproduction technology: a prospective interventional study

PurposeCell-free DNA (cfDNA) as a primary screening test has been available for years but few studies have addressed this option in a prospective manner. The question is of interest after reports that maternal serum screening (MSS) is less accurate for pregnancies resulting from assisted reproduction technologies (ART) than for spontaneous pregnancies (SP).MethodsA prospective interventional study was designed to address the performances of cfDNA compared with MSS in pregnancies with or without ART. Each patient was offered both MSS and cfDNA testing. The primary analysis cohort ultimately included 794 patients with a spontaneous pregnancy (SP) (n = 472) or pregnancy obtained after ART (n = 322).ResultsOverall, the false-positive rate and positive predictive value were 6.6% and 8.8% for MSS but 0% and 100% for cfDNA. MSS false-positive rate and positive predictive values were clearly poorer in the ART group (11.7% and 2.6%) than in the SP group (3.2% and 21.1%). The global rates of invasive procedures were 1.9% (15/794) with cfDNA but 8.4% (65/794) if MSS alone was proposed.ConclusioncfDNA achieved better performance than MSS in both spontaneous and ART pregnancies, thus decreasing the number of invasive procedures. Our findings suggest that cfDNA should be considered for primary screening, especially in pregnancies obtained after ART.     

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

PurposeWe sought to compare measurements of circulating cell-free DNA as well as Down syndrome test results in women with naturally conceived pregnancies with those conceived using assisted reproductive technologies.MethodsData regarding assisted reproductive technologies were readily available from seven enrollment sites participating in an external clinical validation trial of nested case/control design. Measurements of circulating cell-free fetal and total DNA, fetal fraction (ratio of fetal to total DNA), chromosome-specific z-scores, and karyotype results were available for analysis.ResultsAnalyses were restricted to 632 euploid (5.2% assisted reproductive technologies) and 73 Down syndrome (13.7% assisted reproductive technologies), including 16 twin pregnancies. No differences were found for fetal or total circulating cell-free DNA, or for the fetal fraction in euploid (P = 0.70) or Down syndrome (P = 0.58) pregnancies by method of conception. There appeared to be systematic z-score reductions for chromosomes 21, 18, and 13 in assisted reproductive technologies versus natural euploid pregnancies (P = 0.048, 0.0032, and 0.36, respectively).ConclusionAssisted reproductive technologies and naturally conceived pregnancies contribute similar levels of circulating cell-free DNA into maternal circulation. Small differences in the z-scores of pregnancies achieved by assisted reproductive technologies were observed and do not appear to be test-related artifacts. However, the findings need confirmation before any consideration of changes to testing and reporting protocols.     

Noninvasive fetal sex determination in maternal plasma: a prospective feasibility study

PurposeTo prospectively validate a protocol for noninvasive fetal sex determination in maternal plasma and demonstrate its applicability to clinical practice.MethodsPeripheral blood from 404 pregnant women undergoing prenatal invasive testing was collected from 6 to 23 weeks of gestation. Real-time PCR was performed for the SRY gene and multicopy DYS14 marker sequence located within the TSPY gene by the TaqMan minor groove binder probe assay as a first-line test. Owing to a false-positive result, amplification of repetitive motifs of the DAZ gene region was also tested as a second-line test performed in the last 232 patients enrolled in our series. A diagnostic algorithm was designed using a combination of these three markers. Fetal gender determined by noninvasive prenatal diagnosis (NIPD) was compared with that diagnosed by quantitative fluorescent PCR after invasive testing or ultrasound.ResultsA single false-positive result was obtained in the first 172 pregnancies. Reporting criteria were modified in the subsequent 232 pregnancies, giving an overall sensitivity and specificity of 100% (95% CI 99.8–100%) and 99.5% (95% CI 98.1–100%), respectively. Pregnancy outcome was obtained in all cases, including 221 male-bearing and 183 female-bearing pregnancies.ConclusionNIPD for fetal sex determination in maternal plasma is highly accurate and clinically applicable if robust reporting criteria are applied.     

Population-based impact of noninvasive prenatal screening on screening and diagnostic testing for fetal aneuploidy

PurposeTo assess the population-wide impact of noninvasive prenatal screening (NIPS) on combined first-trimester screening (CFTS), early ultrasound (11–13 weeks), and invasive prenatal diagnosis in a state with over 73,000 births per year.MethodsAnalysis of population-based data from 2000 to 2015 including (i) invasive prenatal tests, (ii) CFTS uptake, and (iii) total births. Utilization of early ultrasound was analyzed before and after NIPS (2010–2015).ResultsInvasive testing decreased significantly by 39.6% from 2012 to 2015 despite steady births. More than half of all confirmed cases of trisomy 21 were ascertained by NIPS in 2015, despite NIPS comprising only 11.7% of total indications for invasive testing. CFTS uptake declined significantly from 77.5% in 2013 to 68.1% in 2015, but 11- to 13-week ultrasounds did not. In 2015, ultrasound abnormality replaced CFTS as the most common indication for invasive testing and chromosomal microarray was performed for 85.3% of all prenatal karyotypes.ConclusionPrenatal testing is now unequivocally in the genomic era. NIPS is now the screening test that precedes the majority of confirmed diagnoses of trisomy 21. The contributions of NIPS, early ultrasound, and chromosome microarray have led to unprecedented detection rates of major chromosome abnormalities, now found in 20% of all invasive tests.     

20-year experience on prenatal diagnosis in a reference university medical genetics center in Turkey

Background/aimAlthough cutting edge procedures such as cell-free fetal DNA isolation from maternal blood are now available, invasive prenatal tests are still being used extensively for prenatal diagnosis. The study aims to evaluate the demographic data, indications, and cytogenetic results of 9297 results of patients who underwent prenatal invasive testing for genetic analysis that were referred for the last 20 years in a University Medical Genetics Center.Materials and methodsThe records of 8363 amniocenteses, 626 chorionic villus, and 308 cordocenteses samples were retrospectively evaluated and analyzed regarding referral reasons, indications and their cytogenetic results. The total numbers and the percentages of each group were recorded; Chi-square and logistic regression analyses were performed to give the statistical likelihood of different events. ResultsThe number of referrals decreased significantly after 2009. Risk of having trisomy 21 as well as trisomy 13 and 18 significantly increased in parallel with advanced maternal age. When the 21–25 age group was compared to the older age groups in terms of having a trisomy 21 pregnancy, the risk doubled in the 36–40, 5 times higher in 41–45 and 10-fold in 46–50 age groups. No significant linear correlation between maternal serum screening test results and trisomy 21 was found, however the difference between the pregnancies whom cut-off value above and below 1/250 in maternal serum screening test were significant.ConclusionThese data have provided useful information on the frequency of referrals to the reference genetics department, and the feasibility of genetic services. By reviewing the indications and their corresponding results, we can offer invaluable insights that will be useful in genetic counseling and also in the development of more effective genetic strategies.     

Outcomes in pregnancies with a confined placental mosaicism and implications for prenatal screening using cell-free DNA

PurposeTo assess the association between confined placental mosaicism (CPM) and adverse pregnancy outcome.MethodsA retrospective cohort study was carried out evaluating the outcome of pregnancies with and without CPM involving a rare autosomal trisomy (RAT) or tetraploidy. Birthweight, gestational age at delivery, fetal growth restriction (FGR), Apgar score, neonatal intensive care admission, preterm delivery, and hypertensive disorders of pregnancy were considered.ResultsOverall 181 pregnancies with CPM and 757 controls were recruited. Outcome information was available for 69% of cases (n = 124) and 62% of controls (n = 468). CPM involving trisomy 16 (T16) was associated with increased incidence of birthweight <3rd centile (P = 0.007, odds ratio [OR] = 11.2, 95% confidence interval [CI] = 2.7–47.1) and preterm delivery (P = 0.029, OR = 10.2, 95% CI = 1.9–54.7). For the other RATs, an association with prenatally diagnosed FGR was not supported by birthweight data and there were no other strong associations with adverse outcomes.ConclusionExcluding T16, the incidence of adverse pregnancy outcomes for pregnancies carrying a CPM is low. RATs can also be identified through genome-wide cell-free DNA screening. Because most of these will be attributable to CPMs, we conclude that this screening is of minimal benefit.     

Informatics-based,highly accurate,noninvasive prenatal paternity testing

PurposeThe aim of the study was to evaluate the diagnostic accuracy of an informatics-based, noninvasive, prenatal paternity test using array-based single-nucleotide polymorphism measurements of cell-free DNA isolated from maternal plasma.MethodsBlood samples were taken from 21 adult pregnant women (with gestational ages between 6 and 21 weeks), and a genetic sample was taken from the corresponding biological fathers. Paternity was confirmed by genetic testing of the infant, products of conception, control of fertilization, and/or preimplantation genetic diagnosis during in vitro fertilization. Parental DNA samples and maternal plasma cell-free DNA were amplified and analyzed using a HumanCytoSNP-12 array. An informatics-based method measured single-nucleotide polymorphism data, confirming or rejecting paternity. Each plasma sample with a sufficient fetal cell-free DNA fraction was independently tested against the confirmed father and 1,820 random, unrelated males.ResultsOne of the 21 samples had insufficient fetal cell-free DNA. The test correctly confirmed paternity for the remaining 20 samples (100%) when tested against the biological father, with P values of <10⁻⁴. For the 36,400 tests using an unrelated male as the alleged father, 99.95% (36,382) correctly excluded paternity and 0.05% (18) were indeterminate. There were no miscalls.ConclusionA noninvasive paternity test using informatics-based analysis of single-nucleotide polymorphism array measurements accurately determined paternity early in pregnancy.Genet Med 2013:15(6):473–477     

Genome-wide noninvasive prenatal screening for carriers of balanced reciprocal translocations

PurposeBalanced reciprocal translocation carriers are at increased risk of producing gametes with unbalanced forms of the translocation leading to miscarriage, fetal anomalies, and birth defects. We sought to determine if genome-wide cell-free DNA based noninvasive prenatal screening (gw-NIPS) could provide an alternative to prenatal diagnosis for carriers of these chromosomal rearrangements.MethodsThis pilot series comprises a retrospective analysis of gw-NIPS and clinical outcome data from 42 singleton pregnancies where one parent carried a balanced reciprocal translocation. Gw-NIPS was performed between August 2015 and March 2018. Inclusion criteria required at least one translocation segment to be ≥15 Mb in size.ResultsForty samples (95%) returned an informative result; 7 pregnancies (17.5%) were high risk for an unbalanced translocation and confirmed after diagnostic testing. The remaining 33 informative samples were low risk and confirmed after diagnostic testing or normal newborn physical exam. Test sensitivity of 100% (95% confidence interval [CI]: 64.6–100%) and specificity of 100% (95% CI: 89.6–100%) were observed for this pilot series.ConclusionWe demonstrate that gw-NIPS is a potential option for a majority of reciprocal translocation carriers. Further confirmation of this methodology could lead to adoption of this noninvasive alternative.     

The risk of fetal loss following a prenatal diagnosis of trisomy 13 or trisomy 18

The objective of this study is to determine the risk of fetal loss (spontaneous abortion or stillbirth) following a prenatal diagnosis of trisomy 13 (T13; Patau syndrome) or trisomy 18 (T18; Edwards syndrome). Five regional congenital anomaly registers in England and Wales provided details on the outcomes of 198 pregnancies prenatally diagnosed with T13 and 538 prenatally diagnosed with T18. For each pregnancy the time from prenatal diagnosis until birth, miscarriage or termination occurred was calculated and these times were analyzed using Kaplan-Meier survival functions. Our results showed that between 12 weeks gestation and term an estimated 49% (95% CI: 29-73%) of pregnancies diagnosed with T13 and 72% (61-81%) of pregnancies diagnosed with T18 ended in a miscarriage or stillbirth. Between 18 weeks and term the proportions were 42% (18-72%) for T13 and 65% (57-79%) for T18 and between 24 weeks and term the proportions were 35% (5-70%) for T13 and 59% (49-77%) for T18. Male fetuses with T18 appeared to be more likely to be lost than female fetuses. These are the most precise estimates currently available for the risk of loss in a general population. These estimates should be useful in counseling women who are carrying an affected fetus and knowing the risk of fetal loss is essential to compare the performance of prenatal screening programs occurring in the first and second trimester.