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If the fetus has another chromosomal anomaly which is not trisomy 21, can this be detected by NIPT?
Since the first prenatal genetic diagnosis in 1966, a major focus has been on the detection of trisomy 21. Trisomy 21 is the most visible and most common genetic disorder. The first invasive prenatal diagnosis by conventional karyotyping enabled the detection of trisomy 21. However, karyotyping allowed also the detection of other chromosomal anomalies. In the first place, it allowed for the detection of other chromosomal anomalies. Those include the viable trisomies 13 and 18, sex chromosomal anomalies and also other chromosomal trisomies which are not viable but often cause intrauterine growth retardation or are risk factors for miscarriages. More importantly, segmental chromosomal imbalances could also be detected. The majority of large imbalances visible by conventional karyotyping cause developmental disorders which are more severe compared with trisomy 21. Some viable examples include the Wolf-Hirshhorn and Cri-du-chat syndromes, severe developmental disorders, caused by terminal deletion of respectively the short arms of chromosomes 4 and 5. With ever-improving technologies, gradually smaller imbalances could be detected. The gold standard in invasive prenatal shifted from karyotyping to chromosomal microarrays. Those arrays allow for the detection of submicroscopic microdeletions and duplications. Recurrent microdeletions or microduplications are coined genomic disorders. Recurrent indicates that in different patients the deletion or duplication is exactly the same size. The common breakpoints are a consequence of the mechanism causing the rearrangement: during meiosis, homologous chromosomes align and homologous recombination shuffles the parental variants across the chromosomes while the sequence remains intact. However, some chromosomes carry so called low copy repeats, large chromosomal segments which are present in multiple copies. Because they share the same sequence, pairing can occur at misaligned low copy repeats resulting in microdeletions or microduplications. Genomic disorders are rare, but amongst the most frequent rare diseases. The most frequent genomic disorder is the 22q11 Deletion Syndrome, which occurs in about 1/3000 life-births and an estimated 1/1000 pregnancies. Other genomic disorders occur with a frequency of 1/5000 to 1/100000 pregnancies. The adoption of submicroscopic copy number variation screening increased the detection of potentially significant copy number variants with about 3.5%.
Similarly, to invasive genetic testing, the primary focus of non-invasive prenatal testing has first been the detection of trisomy 21. Gradually, however, we see a broadening of the prenatal testing capabilities, including the detection of both microscopic and submicroscopic imbalances. Both whole genome sequencing and targeted genome analyses NIPT methodologies are including the analysis of genome wide imbalances and/or genomic disorder detection. The value of enabling the detection of other chromosomal trisomies beyond the viable trisomies 13, 18 and 21 remains somewhat controversial. While trisomy 16 is a major cause of miscarriages, the consequences of the other trisomies are not yet fully mapped. The detection of large segmental imbalances is generally considered as an additional benefit of non-invasive prenatal testing. The detection of the smaller segmental imbalances causing genomic disorders is also considered as beneficial and an overall improvement of non-invasive testing. However, there remains a lot of controversy about the clinical utility of implementing this test. Since the detection of genomic disorders is challenging and since the incidence of genomic disorders is low, the positive predictive values are generally lower as compared to trisomy 21 testing. The introduction of those tests comes with a burden of more false positives and hence, an increase in the number of unnecessary invasive tests. Hence, the aim of identifying a broad range of genomic disorders may counteract the aim of non-invasive testing to reduce the number of invasive tests.
Despite these controversies, it seems to be inevitable that the field will move in the direction of detecting more chromosomal imbalances by non-invasive testing. The detection of more anomalies will avoid birth defects which are often more severe than Down syndrome. I think the general public will embrace this expansion of the scope of NIPT.