REVIEW – October 2016

Non-invasive prenatal genetic testing – triumph and shortcomings

Authors: Anne Mari Roost, Tiia Reimand, Kaarel Krjutškov

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Estonia as well as many other European countries provide nationally organized routine prenatal screening for fetal chromosomal abnormalities. Commonly these tests include maternal blood screening in the first and second trimesters along with ultrasound. Despite the 85–90% detection rate for Down syndrome (DS) at the first-trimester screening, about eleven DS children per 10,000 live births are born in Europe each year. These cases are mainly caused by non-participation in screening programmes or by false negative results. Additionally, a large number of women carrying a healthy baby are invited to invasive diagnostic procedures due to false positive results. The American College of Obstetricians and Gynecologists has approved a new method for prenatal chromosomal aneuploidy screening, which has higher accuracy compared to conventional serum screening. Non-invasive prenatal genetic testing, or NIPT, is based on the analysis of cell-free fetal DNA (cffDNA). The CffDNA originates mainly from apoptotic cells in the placenta and is released into maternal blood.

Over 10 NIPT platforms are commercially available worldwide and they all detect the copy number of common aneuploidy-related chromosomes 13, 18 and 21; however, many tests now also test sex chromosomes and some disease-related microdeletions and microduplications. All tests are based either on whole-genome, targeted, or single nucleotide polymorphism (SNP) based analysis. A recent meta-analysis of the performance of cfDNA testing in screening for aneuploidies included data from 37 studies. Weighted pooled detection rates and false-positive rates in singleton pregnancies were 99.2% and 0.09%, respectively, for trisomy 21, 96.3% and 0.13% for trisomy 18, and 91.0% and 0.13% for trisomy 13. Despite the high detection rates, NIPT has been criticized primarily for lack of knowledge and data about testing among general population of pregnant women without a high risk for fetal chromosomal aberrations. Some concern has also been expressed about inadequate counselling before and after women undergo NIPT. Possible solutions to these limitations are combining NIPT with conventional screening methods, but also emphasizing the importance of counselling and the non-diagnostic nature of NIPT.

In Estonia, screening for fetal chromosomal aberrations in women over 35 years of age started in 1995. This was followed by second-trimester serum screening, and in 2005, by combined first-trimester screening in larger hospitals. Currently firstor second-trimester screening is offered to all pregnant women despite their age. The NIPT tests Verifi, Harmony, Panorama, MaterniT21 and VisibiliT can be ordered, in which case the sample is sent abroad to a service-providing laboratory. A wider use of NIPT is mainly impeded by its high cost, as the test prices start from 450€. No NIPT solution is currently covered by the Estonian Health Insurance Fund.

Scientists from the Competence Centre on Health Technologies (CCHT), in cooperation with the University of Tartu, are developing a NIPT platform, which will allow the whole process from blood sample collection to data analysis to be carried out at the newly founded Genetic Testing Competence Centre in Estonia. As a first step, a whole-genome technology based Belgian Leuven University NIPT pipeline will be introduced to start providing highquality NIPT in Estonia.