New genomic laboratory technology namely microarrays and high throughput sequencing (HTS) as well as a steady progress in sonographic image capture and processing have changed the practice of prenatal diagnosis during the last decade fundamentally. Pregnancies at high risk for common trisomies are reliably identified by non-invasive prenatal testing (NIPT) and expert sonography has greatly improved the assessment of the fetal phenotype. Preconceptional comprehensive carrier screening using HTS is available for all parents, if they should wish to do so. A definite fetal diagnosis, however, will still require invasive testing for most conditions. Chromosomal microarrays (CMA) have greatly enhanced the resolution in the detection of chromosome anomalies and other causal copy number variations (CNV). Gene panel or whole exome sequencing (WES) is becoming the routine follow up of many anomalies detected by ultrasound after CNVs have been excluded. The benefits and limitations of the various screening as well as diagnostic options are perceived as complex by many who find it challenging to cope with the need for immediate choices. The communication of facts to ensure an informed decision making is obviously a growing challenge with the advent of the new genomic testing options. This contribution provides an overview of the current practice and policies in Switzerland.
For decades and until today the prenatal diagnosis of chromosomal anomalies and monogenic conditions relies on testing cells obtained by an invasive procedure which poses a small risk to the fetus. Therefore, the access to these procedures has traditionally been more or less strictly limited to pregnancies with an increased risk mainly for aneuploidies as defined by advanced maternal age as the sole parameter for many years. Only a small proportion of pregnancies were tested due to familial genetic conditions or following carrier testing in high risk populations. The performance of risk screening for aneuploidies improved steadily over the years by inclusion of maternal serum parameters in the second trimester and later of the sonographic measurement of the nuchal translucency plus maternal serum parameters in the first trimester (first trimester screening) [1, 2]. High throughput sequencing (HTS) of DNA fragments in the maternal circulation, however, has – unexpectedly – during the past decade set a new performance standard in prenatal screening for aneuploidies which became the first large-scale clinical application of this technology. HTS also for the first time permits the short term diagnostic testing of significant parts of the fetal genome when malformations are found on ultrasound and copy number variants are excluded .
Non-invasive prenatal testing or screening (NIPT, NIPS)
The rapid implementation of non-invasive prenatal testing or screening (NIPT, NIPS) in the developed world was driven by commercial providers mainly from China and the US and the tests became soon extremely popular with parents to be and their attending obstetricians. The initial promise, however, that the NIPT might be diagnostic turned out to be overoptimistic mainly due to a biological phenomenon well-known since the introduction of chorionic villus sampling, i.e. confined placental mosaicism (CPM) which may cause false positive as well as false negative test results [4, 5]. A number of maternal factors may cause false-positive test results . The negative predictive value, however, for trisomies 21, 13 and 18 is very high and a mainstay of the superior performance of NIPT as a screening tool which has caused a significant decrease of invasive procedures worldwide. All screenpositive test results, however, require a confirmation by an invasive procedure . NIPT has been implemented without regulatory guidance in many countries and followed strictly formal protocols in others.
Switzerland was among the first countries where the obligatory health insurance covered the cost for NIPT under certain conditions (contingent screening approach) starting in 2015. In a joint effort of health administration and the professional organisations involved detailed criteria were defined and published (current version as of March 2018 ). They basically restrict the coverage to the screening for trisomies 13, 18, and 21 and a risk of more than 1 in 1,000 in the first trimester combined test and also specify quality criteria for nuchal translucency measurements and risk calculation for the first trimester test. Another requirement is that the test must be performed within the country which induced a collaboration of major providers with local laboratories. First trimester combined testing is part of the routine prenatal care and offered in all pregnancies [9, 10]. Non-invasive test approaches, however, covering the sex chromosomes, selected microdeletion syndromes or any larger CNV have been successfully marketed, are a frequent choice  and billed to the patient. The debate on the clinical utility of expanded NIPT options is ongoing for years and remains controversial . In practice both options have to be addressed in some detail and reimbursement is just one of several aspects relevant to the decision. The future of the current contingent screening approach also remains a matter of controversy which is likely to resolve when testing costs come down.
In the past prenatal or ideally preconceptional carrier screening has been recommended for populations with a known increased risk for recessive conditions. The textbook example is hemoglobinopathies where cost-effective non-genetic screening is available by a red blood cell count and hemoglobin-electrophoresis. In some countries screening for the more frequent recessive conditions is recommended such as cystic fibrosis, spinal muscular atrophy and others [13, 14]. Carrier screening uptake is traditionally high in the Jewish population and a national program provides testing free of charge in Israel . HTS opens up a new dimension of testing options which may be useful for consanguineous couples  or in families with a suspected genetic condition when the index patient is not available. The popular direct to consumer tests cannot be recommended, however, for various reasons and test results must be confirmed .
For the time being there are no specific national recommendations in Switzerland. Carrier tests are not covered by the health insurance and the demand for cost intensive genomic test approaches remains low.
In the last two decades fetal phenotyping by prenatal sonography improved significantly. Prenatal physical and functional symptoms of a growing number of genetic conditions were identified and correlated to specific copy number or DNA sequence variants. Hygroma colli in early pregnancy was one of the first anomalies investigated and confirmed as an important marker of chromosomal and others fetal disorders since the end of the 80s [18, 19]. During the 90s the risk assessment for chromosomal anomalies was based on the so-called genetic sonogram which included the search for major fetal anomalies and softmarkers [20, 21]. The screening performance increased further with the introduction of the combined test earlier in pregnancy at 11–14 weeks [22, 23]. The standardized measurement of the nuchal translucency (NT) became the best and critical marker in first trimester risk screening and required continuous quality control policies .
Following the implementation of the NIPT the role of sonography in the screening for common trisomies was occasionally questioned. All relevant advisory boards, however, stressed the fundamental role of ultrasound in screening for other genetic and non-genetic conditions. For decades two or more ultrasound scans are an established part of antenatal care in most developed countries. In Switzerland and other countries NIPT was integrated in the existing antenatal care schemes i.e. ultrasound scans and NT measurement are recommended as the first step prior to all further testing [9, 24].
The main intention of this policy is to not reduce antenatal screening to common trisomies and use the potential of diagnostic ultrasound for fetal phenotyping. An increased NT has been found as an early sign of a variety of fetal malformations and more than 50 rare syndromes [25, 26]. In a recent study abnormal ultrasound findings in general were associated with copy number variation (CNV) not detected by NIPT in 16.3% of pregnancies . The single most important ultrasound marker for CNVs as well as monogenic conditions is an increased NT (Figure 1) [25, 26]. Numerous groups reported a wide range of CNVs and DNA-sequence variants in presence of major isolated or multiple fetal abnormalities namely increased nuchal translucency (NT≥3.5 mm), cardiac, skeletal, urogenital, renal and central nervous system anomalies (3.5–80%) (Figures 2 and 3) . Based on these findings invasive testing is recommended in Switzerland whenever a fetal structural anomaly is diagnosed, or the NT is increased, or the risk in the combined test is higher than 1 in 10  because the estimated detection rates of advanced genomic testing may be as high as 30% [29, 31, 32].
Since the implementation of NIPT in clinical practice the number of diagnostic procedures, CVS or amniocentesis being the most common, decreased significantly particularly for interventions related to an increased risk for the frequent trisomies based on advanced maternal age only or other low risk indications such as e.g. parental choice. The advantage of the very high negative predictive values of NIPT for the frequent trisomies is the best argument in favour of this approach, and limits invasive testing to confirmation of NIPT findings indicating an increased risk by rapid testing methods such as QF-PCR, FISH or MLPA on digested chorionic villi or amniotic fluid cells, and to differentiate between free trisomies from unbalanced translocation trisomies by consecutive microscopic karyotyping on cultured cells .
However, in the presence of fetal structural anomalies different considerations apply. There is consensus that NIPT should only be offered in combination with a certified ultrasound scan. Increased nuchal translucency is associated with a higher risk of numerical but also structural chromosome abnormalities causing fetal malformations particularly cardiac, genitourinary, skeletal, but also others, not necessarily apparent in first trimester ultrasound scan.
In most countries molecular karyotyping by chromosomal microarray (CMA) has now replaced the conventional microscopic chromosome analysis because of its superior detection rate including clinically relevant submicroscopic structural chromosome changes also termed copy number variants (CNV). Additional 6–10% of clinically relevant CNVs are identified in the presence of increased NT, intrauterine growth restriction and/or one or more fetal structural anomalies, and the risk is increased also following positive FTT screening results due to altered PAPP-A and free beta-HCG levels without fetal anomalies [34, 35]. The detection rate is particularly high in the presence of multiple anomalies or when specific organ systems are affected as e.g. in the presence of brain, cardiac or renal anomalies, or in fetuses with NT>3.5 mm [29, 36], , . NIPT, as a screening tool, has poor positive and negative predictive values for CNVs, and therefore is not indicated in pregnancies at high risk for chromosomal anomalies other than the frequent trisomies. An 1.7% baseline risk for CNVs in low risk pregnancies without fetal anomalies was assessed in pregnancies examined for advanced maternal age and pathogenic CNVs were identified in 0.86–1.7% in pregnancies without any risk factors.
The diagnosis of an unbalanced structural chromosome anomaly, recurrent or rare microdeletion or -duplication syndrome may significantly change the prognosis since global developmental delay and/or intellectual disabilities may be associated, and the etiologic diagnosis influences parental decisions and pregnancy management. Obviously such functional abnormalities cannot be detected by ultrasound. After the exclusion of the frequent trisomies by rapid testing using QF-PCR, FISH or MLPA on the invasive sample, CMA analysis is performed on DNA extracted from digested chorionic villi, native amniocytes or cultured cells depending on the quantity of DNA available from the native sample provided. All other considerations for standard karyotyping including quality measures minimizing the risk for maternal contamination as well as guidelines assessing and interpreting mosaicism of the fetoplacental unit also apply for CMA analysis. In addition to the detection of CNVs using common oligo-arrays for array comparative genomic hybridization, also known as array-CGH, microarrays including additional single nucleotid polymorphisms (SNPs) allow the detection of triploidy and uniparental isodisomy. In most diagnostic laboratories CNVs up to a 100–200 kb size, representing a resolution 100× higher than microscopic karyotyping, are reported. Balanced chromosomal abnormalities cannot be detected by CMA, since there is no loss or gain of genomic material in a truly balanced rearrangement.
In many countries, including Switzerland, CMA has now replaced conventional karyotyping in the presence of ultrasound anomalies or on parental request. Pre- and posttest counselling remains important and gets more complicated regarding todays’ multiple testing options in various clinical settings. Besides benefits and limitations challenges of genomic testing by CMAs such as copy number variants of unknown significance need to be addressed, although estimated to occur in only about 1% now with the increasing experience on CNV interpretation  and parental analysis being helpful for interpretation. Variable penetrance and unsolicited findings generating potential familial implications for late manifesting disease complicate patient counselling in an emotionally fragile situation when fetal anomalies are detected.
When there is no chromosomal abnormality or pathogenic CNV identified, HTS now facilitates the parallel sequencing of multiple genes to identify pathogenic sequence variants causing monogenic disorders. While such sequencing approaches allow to sequence the coding genome (the exome, representing about 1% of the genome) or even the entire genome, in only 7,000 of the 22,000 genes of the exome multiple, but not all, variants are known to cause a monogenic disorder for the time being, often also called the «mendeliome». Balancing the wealth of data technically obtainable against the primary goal of prenatal diagnosis to identify a reliable etiologic and prognostic information in a reasonable time frame several HTS approaches can be used. These include the interpretation of variants in a restricted and predefined number of disease genes for which there is evidence for a causal relationship to the phenotype, often also termed panel-sequencing. This approach has e.g. been used for the diagnosis of skeletal dysplasias which are a heterogeneous group of diseases with overlapping clinical signs identified by ultrasound scan  achieving a high diagnostic yield when combining the analysis of sequence data with expert clinical genetics reviews. Another strategy is to include variants present in all known disease genes in a clinical exome (CES) as opposed to all genes in a whole exome (WES) including those not yet linked to a human phenotype. Trio-exome sequencing including samples of the parents is often used to facilitate variant interpretation and shorten turn-around-time.
Panel and CES approaches are on the verge of being implemented into routine clinical practice when there is increased NT, hydrops, intrauterine growth restriction and/or a single or multiple congenital anomalies in the presence of a normal CMA result as a sequential test. The consideration is based on postnatal WES which allows a diagnosis in about 25% of patients with various indications  and such will be present already prenatally. There are so far only a few prospective studies assessing the prenatal diagnostic yield for monogenic disorders which varies considerably according to the clinical phenotype. The PAGE study (and substudies) revealed the high detection rate of 15.4% for fetuses with multiple congenital anomalies, skeletal and cardiac defects [31, 32, 41, 42]. Monogenic causes for isolated increased NT in the first trimester were identified in 3.2% of pregnancies and 25% in non-immune hydrops fetalis phenotypes. Pathogenic variants in genes involved in the rasopathy pathway causing hydrops as the severe end of the Noonan syndrome phenotype spectrum seem to account for the majority of cases in the current studies [41, 43]. Retrospective studies for selected indications and in small patient series using various sequencing approaches show diagnostic yields between 6.5 and 80% (reviewed by ).
It is important to mention that neither CMA nor genome-wide sequencing approaches will detect all genetic disorders or exclude them entirely. The residual risk for a rare disorder, especially in the presence of multiple congenital anomalies, is an important aspect of patient counselling. Particularly sequencing approaches for monogenic disorders are still incomplete by missing certain types of variants in known disease genes, and by the presence of variants of unknown significance which we cannot reliably interpret in the context of human disease. Furthermore, our knowledge about phenotype-genotype correlation so far mainly relates to postnatal experiences, and the fetal phenotype presentation may be more severe, lethal, different or incomplete as compared to the postnatal presentation even if caused by variants in the same gene or even identical variants . Reporting or disclosure of incidental or secondary findings or pathogenic variants for late-manifesting disorders in the fetus and the parents remain a challenge particularly in a prenatal application , , , . Several professional societies have established recommendations for prenatal exome sequencing and counselling trying to standardize the clinical implementation and address all these uncertainties [50, 51].
There is now a multitude of screening and testing options in prenatal medicine (Figure 4). Emerging technologies such as optical mapping  or whole genome sequencing as the ultimate «one test for all» will overcome the technical difficulties of applying several methods sequentially by its ability to detect chromosome abnormalities, CNVs and sequence variants at the same time but will likely require an invasive procedure. Non-invasive prenatal diagnosis is established to determine the fetal sex or Rhesus type and is offered in some specialized laboratories for more frequent dominant new mutations and some specific familial variants. Prenatal medicine is turning into precision medicine which, however, will only be beneficial for patients when there is a close interdisciplinary collaboration of maternal fetal medicine specialists, clinical geneticists and genomic laboratories in order to maximize the benefit of technological advances for a specific clinical question and to limit the potential harms, ensuring appropriate patient counselling and care.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
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