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Missed diagnoses of abnormal copy number variant cases: A national epidemic or an endemic at a single institution?

A. Ghidini,L. Chitty

Published 2018 in Prenatal Diagnosis

ABSTRACT

The article by Evans et al, published in this issue of Prenatal Diagnosis, was originally presented at the 2017 International Society for Prenatal Diagnosis meeting, where it generated a lot of discussion. The article stems from the observation that the improved predictive ability of noninvasive genetic screening tests for Down syndrome has resulted in a sharp decrease in the use of invasive diagnostic testing. This is at a time when invasive diagnostic tests have led to an improved ability to detect de novo microdeletions and microduplications (pathologic copy number variants, CNVs) using microarrays. The authors feel that obstetricians are doing a disservice to their patients by emphasizing the accuracy of noninvasive prenatal screening for Down syndrome, while not emphasizing enough the probability of detection of pathologic CNVs with invasive diagnostic testing. As editors, and having heard the arguments at International Society for Prenatal Diagnosis, we think that these issues need to be aired and feel it appropriate to present a critique alongside this commentary. To calculate how many CNVs have been missed, at the authors' hospital and nationwide, the authors do quite a bit of mathematical modeling. The first calculation is to detect how many abnormal CNVs were missed during the study period had the referrals for genetic counseling not declined. It is fair to assume that such women would be similar to the sample that underwent counseling. But then the authors do additional modeling: what if all women at their hospital had undergone genetic counseling? To assume that the rates of acceptance of invasive diagnostic procedures and of abnormal CNVs detected in the remainder population would be the same as in the referred population is unproven. At the authors' institution, the rate of women requesting invasive genetic diagnostic testing after genetic counseling held steady at 80% over the study period. Such a high rate may reflect a selection bias of women already more inclined to undergo invasive testing, which of course implies referral for genetic counseling services. The authors do not provide any comparison between the population which underwent genetic screening and the remainder of the pregnant population delivered at their institution to document similarities in demographic, ethnic, or socioeconomic factors, which are known to account for a different uptake of invasive testing. Another possible selection bias is in the indication for referral to genetic counseling, which is not provided in the study. Given the number of deliveries at the authors' institutions (5000 deliveries), the number of patients undergoing genetic counseling was about 10% of

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