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The controversy surrounding sex chromosomal abnormality reporting

A message from the editor: Prof. Joris Vermeesch, Ph.D.

Sex chromosome aneuploidies (SCAs) are amongst the most frequent chromosomal abnormalities occurring during pregnancy. Rather than having two X chromosomes (females) or an X and a Y chromosome (males), the fetus having an SCA carries either only a single X chromosome (X0, Turner syndrome), three X chromosomes (XXX, Triple X syndrome), two X chromosomes and a Y chromosome (XXY, Klinefelter syndrome) or one X and two Y chromosomes (XYY, XYY syndrome). In addition to full sex chromosomal aneuploidies often segmental chromosomal aneuploidies are observed resulting in similar phenotypes. A staggering 1.8% of all pregnancies present with SCAs of which the large majority, about 80%, are monosomy X. Only ~0.5% of all fetal monosomies X result in live births, others make the bulk of spontaneous miscarriages. The sex chromosomal trisomies are rare in miscarriages and the large majority (90%) of fetuses develop to term. Interestingly, in contrast to the autosomal trisomies, monosomy X incidence does not increase with maternal age.

Overall, the live birth incidence of sex chromosome aneuploidies is about 0.2%, higher than trisomy 21. With such a high incidence, why is non-invasive sex chromosomal aneuploidy testing not on top of the agenda? Why are only some laboratories and only some tests reporting sex chromosome aneuploidies? There are clinical and technical/biological reasons for this ambiguity in reporting, testing and guidelines.

Let’s start with clinical reasons. In contrast to trisomy 21, the phenotype of a sex chromosome anomaly is mild. The XXX, XXY or XYY carriers live a normal life and are virtually undistinguishable from the normal population. Since carriers have three copies of SHOX1, a major determinant of a person’s length and located at the tip of both the X and the Y chromosome, individuals are on average taller compared to the normal population. Triple X syndrome individuals have a slightly lower IQ and anxiety and depression is more common. The XYY individuals may present with learning difficulties. Klinefelter syndrome patients are infertile. However, the large majority (>70%) of XXY, XXX and XYY carriers are never diagnosed. Arguably, the mere presence of a trisomy is not a valid reason for pregnancy interruption. Moreover, early detection could result in stigmatization of those children and reduce their self-esteem. Turner syndrome individuals often present with a short and webbed neck, low set ears, and, because they are missing a copy of SHOX1, short stature. These patients are infertile. To treat the short stature and sexual developmental anomalies often growth hormone or estrogen replacement therapy are administered. There is discussion about the value of early detection of these cases since early Turner syndrome detection may allow for early intervention.

However, in addition to the ambiguous clinical utility of sex chromosomal aneuploidy detection, there are several technical challenges. First, females carry with age increasing amounts of white blood cells with only a single X chromosome. While this number at the reproductive ages averages between 2 and 3% of all cells, those numbers vary significantly amongst women. While those numbers appear small, this is coming close to the fetal fraction in the maternal blood which is measured by NIPT. The result of NIPT for a female pregnancy with a fetal fraction of 6% in a mother with 6% of the white blood cells having monosomy X and normal fetus would be identical as for a mother with 0% but a fetus with 100% monosomy. Most NIPT tests cannot discriminate this biological maternal variation from fetal monosomy X. As a consequence, there are a high number of false positives. Second, Turner syndrome often presents as chromosomal mosaicism. The fetus carries a normal diploid cell line while a significant number of cells are monosomy. In another iteration, the fetus is fully Turner syndrome, but the placenta carries a mixture of normal disomic and monosomic cells. As a consequence, the NIPT measuring the placental constitution will classify the pregnancy as normal. Because of this phenomenon, sex chromosomal NIPT also results in a significant number of false negatives. While studies of the number of false negatives are lacking, several studies have evaluated the false positive rate as well as the positive predictive values of NIPT. Those PPV range between 20 and 25% for Turner syndrome, between 50 and 75% for Triple X syndrome and between 80 and 90% for Klinefelter syndrome. Hence, for every positive NIPT indicating a Turner syndrome fetus there are three to four unnecessary invasive tests.

It can be concluded that NIPT-based SCA testing cannot be used as a diagnostic method, and performing an invasive confirmation test on NIPT-based SCA-positive cases is a must. Since Turner syndrome is so common early in pregnancy and the spontaneous miscarriage rate is high, the clinical validity still has to be proven. In addition, also the clinical utility requires scrutiny. The question remains whether the harm and costs induced by an increased number of invasive testing resulting from NIPT-based SCA testing is in balance with the benefits. Clinicians need an extensive discussion including potential benefits, pitfalls and reproductive options with women prior to the inclusion of SCA based NIPT. This is challenging given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. Both the European and American societies of human genetics recommend against routine screening while the international society of prenatal diagnosis says that SCA should be optional and only be performed with informed consent.