In case you missed it: The prenatal diagnosis editors bring you the most significant advances of 2018

This year, the editors of Prenatal Diagnosis met on an October sunny day in Bethesda, Maryland, to make plans for the journals next year (Figure 1). Following our tradition first established 6 years ago, we discussed what we felt was some of the exciting new advances in prenatal screening and diagnosis. We hope our readers will enjoy reading our overview on the hot topics of 2018, including expanded carrier screening, the role of preimplantation genetic screening prior to in vitro transfer, the value of prenatal exome sequencing in fetuses with structural abnormalities, as well as annual updates in fetal surgery, noninvasive prenatal testing (NIPT), and fetal gene therapy. Seven years after its introduction into clinical prenatal care, over 10 million NIPT have been completed globally.1 Remarkably, 70% of the tests to date have been done on Chinese women. While the majority of cell-free DNA tests are performed for the common fetal autosomal and sex chromosome aneuploidies, the test menus have expanded to include microdeletions, copy number variations, and single gene disorders.2-9 In an extraordinary study published in October 2018, Liu and colleagues performed a large-scale population analysis using shallow sequencing data from 141 431 NIPTs performed at the Beijing Genome Institute in Shenzhen.1 They analyzed these data to track the migration of different population subgroups within China. Using genome-wide association studies they identified a novel gene, NRG1, that is, associated with predisposition to twin pregnancies. They also demonstrated the presence of unique patterns of circulating viral DNA that were associated with a high prevalence of hepatitis B, human herpes viruses 5 and 6, human parvovirus B19, and other clinically important infections. Finally, they identified multiple genes that are associated with height and body mass index in the Chinese population, as well as fertility as a function of maternal age. In summary, noninvasive prenatal DNA sequencing test results can serve as a novel resource for understanding population genetic variation and to identify genotype-phenotype associations. One of the main reasons that NIPT has become incorporated so quickly into prenatal care is that a negative test result has a greater than 99% negative predictive value. For pregnant women who only want reassurance that their baby does not have one of the common autosomal trisomies, (i.e. trisomy 13, 18 or 21) a negative screening result is enough information, and they subsequently decline a diagnostic procedure. This has resulted in a 70% decrease worldwide in amniocenteses and chorionic villus samplings, providing proof of clinical utility for NIPT. A significantly decreased number of diagnostic tests has reduced health care costs, but it has also been assumed that integration of NIPT into care would also be safer for pregnant women and their fetuses because there would be fewer procedure-associated miscarriages. To test this hypothesis, a randomized clinical trial was conducted in 57 centers in France between April 2014 and April 2016 (ClinicalTrials.gov identifier: NCT02127515).10 Two thousand fifty-one pregnant women at high risk of having a fetus with trisomy 21 either received an immediate invasive diagnostic test or first received a cell-free (cf)-DNA test, with invasive testing only performed for a positive screening result. Interestingly, the cfDNA test had a detection rate of 100%. Over 97% of the enrolled subjects who had an initial test (n = 1997) completed the trial. The primary outcome showed that the rate of miscarriage was not statistically different between the two groups (both groups had miscarriage rates of 0.8%), although the authors suggested that the study may have been underpowered to find clinically meaningful differences in losses before 24 weeks of gestation. There were, however, 11 chromosomal abnormalities detected by karyotyping in the group that went directly to invasive testing. Three were apparently balanced translocations without clinical manifestations, one was confined placental mosaicism for trisomy 12, two were mosaic trisomy 13 cases, three were sex chromosome aneuploidies, and two were complex rearrangements expected to be associated with developmental disabilities. Some limitations of this study include the fact that 24% of women initially randomized to the invasive testing dropped out of the study, cfDNA testing was only performed for trisomy 21, and there was a 5.6% false positive rate for the cfDNA group, which led to more diagnostic procedures. As cfDNA sequencing moves towards first tier testing for fetal aneuploidy, it is reasonable to assume that there will be more studies such as this one that will more deeply investigate its clinical utility and the benefits of testing beyond its superior positive predictive values to the current approach of serum screening and nuchal translucency measurement. Expanded carrier screening (ECS) has seen quite an evolution in the last few years, and 2018 has not been an exception. Since its introduction 10 years ago, ECS has been driven mainly by commercial laboratories, which have selected the conditions to be included in the panels based on unclear criteria, often driven by competition to include as many disorders as possible. The most recent publication confirmed that the larger the number of disorders screened, the higher the likelihood of identifying a carrier (as high as 36% for a panel inclusive of 218 diseases).11 Professional organizations have published consensus-determined points to consider when ordering ECS, based on severity, age of onset, consistent phenotype, carrier frequency, and accuracy of the screening test, among other metrics.12 However, when verified, only 27% of the conditions on commercially available ECS panels meet such criteria.13 Since clinicians often do not have the time and genetic expertise to translate such points into customized list of conditions appropriate for prenatal screening, the American College of Obstetrics and Gynecology (ACOG) has suggested a list of 22 conditions that are considered reasonable for inclusion in an ECS panel based on the above-mentioned criteria.14 Currently both ethnicity-based screening and ECS testing are considered acceptable strategies by ACOG.14 However, the conclusions of an initial mathematical modeling, which suggested that ECS would detect more fetuses at risk for severe or profound conditions across all ethnic groups than screening based on ethnicity,15 have partially been confirmed by a few studies, two of which were published in 2018.11, 16 One of such studies compared the screen positive rate of a “standard panel” of 23 conditions (inclusive of most of those suggested by ACOG) with that of a “global panel” of 218 conditions.11 The screen positive rates were 13% and 36%, respectively. However, the 12 most commonly conditions detected by the global panel (ie, those with a positive rate of 1% or greater) included those suggested by ACOG, in addition to three conditions mild or amenable to neonatal screening and treatment and nonsyndromic hearing loss related to mutations in GJB2. In the second study, nine of the 15 couples found to be at risk based on a commercial panel of 100 genetic diseases would have been identified through the ACOG-suggested panel16 the missed conditions were Pompe disease (glycogen storage disease type II), familial Mediterranean fever, GJB2-related nonsyndromic hearing loss, and two mild conditions (achromatopsia and familial Mediterranean fever). It appears that the optimal balance has not yet been achieved; couples are still are risk for undue anxiety and for spending time and money on follow-up testing for mild conditions or conditions with low screening performance. Any benefits of ECS would be mediated by how parents use the information provided by the ECS panels. In 2018, initial data regarding reproductive outcomes of couples that undergo ECS have been published. A survey of 537 couples, in which both partners were identified as carriers for the same autosomal recessive condition, classified as profound, severe, or moderate based on published criteria, found that disease severity had a significant association with changes in decision-making.17 The study was potentially biased by the low response rate (12%). Pregnancy status is another important variable that predicts whether ECS translates into decision-making. Studies originating from IVF clinics have found that 100% of couples in which both partners carry pathogenic variants of the same gene elect to screen embryos through pre-implantation genetic testing, independently from the severity of the condition.16, 18 In contrast, among those screened during pregnancy, only 37% elect prenatal diagnostic testing for that pregnancy.19 A survey of pregnant women's perspectives on ECS confirms such findings: about 42% were unsure what they would do if they discovered their fetus had a genetic disorder, 34% would continue the pregnancy and prepare for the birth of an affected child, and only 24% would likely terminate their pregnancy.20 The study also highlighted the deficit in knowledge of pregnant women. In the study, ECS was proposed in a standardized way with pretest genetic counseling. Among the 50% of women who declined ECS, the most quoted reason (selected by 77% of participants) was that they had no family history. Since ECS screens for monogenic recessive disorders, family history would not be expected to be informative; conversely, women with a positive family history would not be good candidates for ECS, as they would require genetic assessment of their own specific risk and appropriate testing. What kind of information do patients receive related to ECS? Since many healthcare providers lack genetic knowledge to deliver appropriate pretest counseling, are hindered by time constraints and workload and are fearful of overloading prospective parents with too much information during a consultation, couples may go directly to the ECS websites to gather information on conditions tested, potential benefits, and limitations of the screen. A study conducted a comprehensive online search to analyze the content of marketing materials on ECS providers' websites, most of which were commercial.21 Making an informed decision about ECS would require providing neutral information about ECS, nondirective offers of testing, and informed decisions about disorders to be screened. The authors found that there are wide variations in the way ECS is offered, with some sites being quite directive. Most ECS providers offered complimentary genetic counseling to their consumers, although this was often optional, limited to the post-test context, and, in some cases, appeared to be available only to test-positive individuals. Limitations of ECS were usually downplayed, such as the uncertainties involved with many of the conditions screened in ECS panels, including the variable age of onset for some conditions, phenotypes that are not clearly defined, conditions that are not recommended for general population screening in current screening guidelines, and rare conditions for which risk after negative screening results is not known. The above issues are being debated at the same time as innovations are being introduced in ECS, which is moving from targeted mutation screening to genome sequencing of gene-disorder pairs.22, 23 This new technology may improve the sensitivity of detecting clinically significant variants. Since the initial publication in 2015 by Greco and Colleagues,24 that demonstrated that transfer of mosaic aneuploid embryos at preimplantation genetic testing for aneuploidy (PGT-A) can lead to the birth of apparently healthy babies, there have been at least six other studies that reaffirm this finding.25-30 The transfer of a mosaic embryo does not always lead to a live birth and in fact carries with it a greater likelihood of miscarriage and lower birth rates compared with the transfer of nonaneuploid embryos.25-30 The most recent study by Zhang and coworkers showed a live birth rate of 43.5% in the mosaic whole chromosome aneuploidy group compared with 59.1% in the euploid embryo group (P = 0.02).30 This rate is consistent with that reported in other studies.26, 28 Given that some mosaic embryos will result in a normal outcome and others will not, Spinella et al29 looked for additional predictors that would assist in identifying which mosaic embryos have the best reproductive potential. Their prospective study revealed significantly better clinical outcomes in embryos with lower mosaic aneuploidy proportions (ie, with mosaicism in less than 50% of the biopsy cells) compared with those with a higher proportion of abnormal cells (>50%). 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