Assessment of prenatal karyotypes

J.J. van der Smagt1, G.C. Beverstock, M.H. Breuning, H.H.H. Kanhai and F.P.H.A. Vandenbussche

Department of Clinical Genetics, Leiden University Medical Center (LUMC), Department of Obstetrics and Gynecology, Leiden University Medical Center (LUMC), Leiden, The Netherlands

Dear Sir,

With great interest we have read the recent paper by Evans et al. (1999). The authors have calculated how many chromosomal abnormalities would have been missed if a hypothetical fluorescent in-situ hybridization (FISH) probe panel, with a 100% detection rate of chromosome 21, 18, 13, X and Y aneuploidies, had been used instead of formal karyotyping. Approximately 30% of the abnormal karyotypes would not have been detected, leading the authors to conclude that the use of these FISH probes can only be as an adjunct to karyotyping and not as an alternative.

Given the rather low incidence of detectable chromosomal abnormalities, even in so-called high risk groups, very large data sets are required to evaluate the risk of false negative outcomes of any alternative approach to full karyotyping. Indeed, large retrospective studies, such as the one of Evans et al., are the only practical way to tackle this problem. However, despite the huge amount of cytogenetic data that Evans et al. were able to accumulate, we believe that their study may have some serious shortcomings.

Firstly, probably because the study was a collaborative effort, the authors were unable to divide up their 146 000 cases into different groups according to referral. While FISH may be a feasible alternative to karyotyping for a certain subset of women, it is certainly not the case for others. The inclusion of all referrals for prenatal diagnosis in the study is confusing, since it will be clear immediately that in the case of a familial chromosomal rearrangement, karyotyping is dictated by reason. Likewise, once structural abnormalities on ultrasound have been identified, a negative FISH result, using the above set probes, would not be sufficiently informative.

Secondly, and most importantly, in this study the outcome has not been sufficiently defined, other than `abnormal karyotype'. As an abnormal karyotype does not necessarily predict adverse health consequences, the authors have had to resort to estimating that roughly half of the undetected cases may have been of `direct clinical significance'. This estimation may be too high, particularly since all viable trisomies had already been excluded. This is also not in agreement with data from pooled cytogenetic studies in liveborn children (Hsu, 1998Go). From these studies it would seem that less than one third of the autosomal aberrations, after exclusion of trisomy 21, 18, and 13, is in fact aneuploid. Moreover, a significant proportion of these remaining non-trisomy 21, 18 or 13 aneuploids, will be potentially detectable with the FISH probe panel (unbalanced Robertsonian translocations if non-centromeric probes for 21 and 13 are used), or may be without phenotypical consequences to the child (e.g. small supernumerary markers).

The authors failed to report what percentage of missed cases actually ended in termination of the pregnancy as a result of the abnormal finding. As the decision whether or not to interrupt the pregnancy is the most important direct consequence of any first or early second trimester prenatal diagnosis, failing to consider or report this makes it almost impossible to evaluate the importance of the missed cases.

The authors further argue that the abnormal karyotypes, even if they are of no consequence with respect to the phenotype of the fetus, will be of importance for future genetic counselling. Although this may be true for a significant proportion of the cases, it is a matter of debate whether ascertaining families for genetic counselling in itself should be a goal of prenatal diagnosis programmes. Moreover, it must be noted that a proportion of the missed abnormal karyotypes in this study is likely to have been both inconsequential to the fetal phenotype and irrelevant for future genetic counselling. For example, if a normal FISH result would have been reported in a case of confined placental mosaicism, patient anxiety would have been avoided, invasive reinvestigations would not have to be performed, and there would be no obvious need for genetic counselling.

Of all women undergoing prenatal testing, the largest group is referred because of maternal age. The increased risk of having a handicapped child with a chromosomal abnormality that these woman have, when compared with younger women, is almost exclusively caused by the trisomies that are detected by the FISH probes for 21, 18 and 13. Other maternal age-related chromosomal aberrations (e.g. trisomy 16), seldom lead to viable offspring. In other words, from a theoretical viewpoint, it can be expected that by using this FISH probe panel, the risk of chromosomal abnormalities in children of women with increased maternal age can be reduced to that of women, who, because of their age, are not eligible for invasive prenatal diagnosis.

Moreover, since only part of mental retardation and birth defects are caused by detectable chromosomal aberrations, it can be theorized that complete karyotyping will only yield a very small additional reduction of the overall risk of having a handicapped child, once the above-mentioned trisomies have been ruled out by FISH.

Evans et al. predict that the FISH approach will not be cost-effective. Indeed considerable savings in both time and money could be outweighed by the high health care expenditures for liveborn children with a chromosomal abnormality, even if their numbers are relatively small. However, if one chooses to look at this issue from an economical point of view, it would be an oversimplification to just subtract these expenditures from the savings, as much will depend on how the savings will be used. If these savings were used to make testing available to a larger group of pregnant women, or to facilitate other methods of antenatal screening (e.g. ultrasound), this would be likely to lead to an increased detection of relevant abnormalities. Therefore, it remains to be seen whether offering full karyotyping to women referred for maternal age will prove to be our best option in the long run.

For the sake of the argument, we have been assuming, like the authors, a 100% reliability of FISH in detecting trisomy 21, 18 and 13. Unfortunately reports on the sensitivity of FISH are conflicting and large numbers of uninformative samples have been reported (Ward et al., 1993Go; Bryndorf et al., 1997Go).

Therefore, while it remains important to evaluate `false negatives' in large retrospective studies, at the same time the applicability of large-scale use of a FISH probe panel in the standard prenatal diagnosis setting has to be further evaluated prospectively.

Meanwhile, the results of the study by Evans et al. do not provide a definite counter argument against the use of FISH as a potential alternative to full karyotyping in women referred for maternal age.

Notes

1 To whom correspondence should be addressed Back

References

Bryndorf, T., Christensen, B., Vad, M. et al. (1997) Prenatal detection of chromosome aneuploidies by fluorescence in situ hybridization: experience with 2000 uncultured amniotic fluid samples in a prospective preclinical trial. Prenat. Diagn., 17, 333–341.[ISI][Medline]

Evans, M., Henry, G., Miller, W. et al. (1999) International, collaborative assessment of 146 000 prenatal karyotypes: expected limitations if only chromosome-specific probes and fluorescent in situ hybridization are used. Hum. Reprod., 14, 1213–1216.[Abstract/Free Full Text]

Hsu, L. (1998) Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In Milunsky, A. (ed.), Genetic Disorders and the Fetus. Diagnosis, Prevention and Treatment. Johns Hopkins University Press, Baltimore, USA, pp. 179–248.

Ward, B., Gersen, S., Carelli, M. et al. (1993) Rapid prenatal diagnosis of chromosomal aneuploidies by fluorescence in situ hybridization: clinical experience with 4,500 specimens. Am. J. Hum. Genet., 52, 854–865.[ISI][Medline]





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