Abstract
In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.
Highlights
Introduction and OverviewThe search for prenatal detection of chromosomal anomalies has been ongoing since the 1960s
Even though the performance of non-invasive prenatal testing (NIPT) is dependent on prevalence i.e., maternal age dependent, overall performance is excellent and superior to first trimester combined screening in the high risk cases and in the general population, in particular for trisomy 21 [8,9]
A recent study showed that management would be changed in almost 10% of cases, when ultrasound was done before blood for NIPT was drawn [15]
Summary
The search for prenatal detection of chromosomal anomalies has been ongoing since the 1960s. In addition to NIPT screening for common trisomies and sex chromosomal anomalies, some companies have added copy number variants to their screening panels Some have limited their approach to specific microdeletions, for example Di George syndrome (22q11.2), which is the most prevalent microdeletion syndrome with a well-known and highly variable phenotype [78]. Multiple aneuploidies/complex abnormal NIPT results have been described in cases of maternal malignancy occurring during the current pregnancy This phenomenon as an accidental finding is linked to rare autosomal trisomies but may include multiple common chromosomal anomalies or fragmented DNA gains and losses [97]. For pregnant women with known malignancy, NIPT is not recommended
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