Cell‐free DNA testing for 22q11.2 deletion syndrome: appraising the viability, effectiveness and appropriateness of screening

In this issue of the Journal, Gross and colleagues present results from the first 6 months of clinical testing for 22q11.2 deletion syndrome (22q11.2 DS) using a single-nucleotide polymorphism (SNP)-based cell-free DNA (cfDNA) assay1. In contrast to the numerous clinical validation studies published in rapid succession on cfDNA screening for Down syndrome, data on the new practice of microdeletion screening have been slow to appear, despite it now having been available commercially for over 2 years. This study is only the second large-scale report of cfDNA screening for 22q11.2 DS in clinical practice, and, as such, provides important information on the expansion of cfDNA beyond the common autosomal aneuploidies. In this retrospective cohort study of 21 948 women referred for 22q11.2 DS screening, 5.3% were excluded due to their sample being unsuitable. Of the remaining 20 776 women, 92.1% had low-risk calls, 7.4% had results equivalent to the population risk (‘risk unchanged’) and 0.5% (n = 97) had high-risk calls for 22q11.2 DS. Importantly, this study was not designed to clinically validate the sensitivity and negative predictive value of cfDNA screening for 22q11.2 DS. Rather, the study had the more modest objectives of assessing rates of follow-up diagnostic testing and clinical outcomes in the 95 cases with a suspected fetal deletion. Forty-eight of the 84 women known to have been provided information on invasive testing elected to have prenatal diagnosis (57% uptake). Results of prenatal and postnatal diagnostic testing were available for 61 of the high-risk cases, with 11 (18%) being confirmed on karyotyping or molecular testing as true positives. Eight of these 11 women had fetal ultrasound abnormalities detected prior to cfDNA screening. As the authors acknowledge, one of the limitations of this study was the incomplete follow-up of women with high-risk results: data on confirmatory diagnostic testing were missing in 36% of cases and final pregnancy outcome was unavailable for 30.5%. Unfortunately, this precludes any precise assessment of the accuracy of SNP-based screening for 22q11.2 DS, or the drawing of firm conclusions about its effect on key outcomes such as newborn management and termination of pregnancy. The overall rate of termination of pregnancy for the total cohort is unknown; only three women were known to have terminated their pregnancy as a direct result of screening, but it is possible that more terminations occurred in the cases that did not participate in follow-up. Another limitation of the study was the lack of outcome data in women with low-risk screening results. Therefore, the sensitivity and the negative predictive value of screening in clinical practice remain unconfirmed. Although clinicians were encouraged to report cases that were missed by screening, placing the onus on clinicians to report false-negative screening results for 22q11.2 DS is inadequate as many children with a mild phenotype will not be diagnosed in the newborn period (see Appendix). Furthermore, the relatively low prevalence of 22q11.2 DS means that a study even of this size (approximately 20 000 women) may still be insufficiently powered to produce a precise estimate of test sensitivity.