Chances and Challenges of New Genetic Screening Technologies (NIPT) in Prenatal Medicine from a Clinical Perspective: A Narrative Review

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.

Clinical Application of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies in Central China

“…There are many methods for screening for trisomy 21, trisomy 18, and trisomy 13, including maternal serum screening (MSS), ultrasound, and noninvasive prenatal testing (NIPT) ( 4 ). In contrast, limited methods can be used to screen SCAs, as the clinical features of most SCAs are not detectable during prenatal ultrasound examination because many develop after birth with the exception of structural anomalies more commonly seen in the Turner syndrome ( 1 , 5 – 7 ). With the discovery of circulating cell-free fetal DNA (cffDNA) in the blood samples of pregnant women and the advent of massively parallel genomic sequencing (MPS) technology, NIPT has been widely applied for the clinical screening for fetal chromosomal aberrations and has already expanded beyond the three common autosomal trisomies to include SCAs ( 8 , 9 ).…”

The ethical landscape(s) of non-invasive prenatal testing in England, France and Germany: findings from a comparative literature review

“…In Germany, the debate on reproductive autonomy in the context of NIPT often focuses on the woman’s right not to know’ or her right to decline available prenatal tests [ 27 – 29 ]. It is also suggested that, in addition to information provided by professionals, a woman should be put in contact with associations or families who have a child living with a trisomy [ 6 , 30 ], so, she is able to make a fully informed decision about whether to continue or terminate her pregnancy.…”

Validity and Utility of Non-Invasive Prenatal Testing for Copy Number Variations and Microdeletions: A Systematic Review

“…Fetal DNA analysis is the only method for detecting these disorders. The correlation between an elevated risk for pathological copy number variations and increased nuchal translucency, as well as altered serum levels of PAPP-A and free β-HCG, was noticed [ 1 , 2 ]. Other than these, the main indications for wide NIPT analysis are previous children with chromosomal alterations, the sonographic detection of fetal abnormalities, and a history of family members testing positive for chromosomal or genetic disorders [ 3 ].…”