Reply

Abstract

We thank Drs Jing and Li for their thoughtful comments on our study1 and their reflections on prenatal screening for 22q11.2 deletion. They raise important points on which we would like to comment further and provide clarification. Drs Jing and Li suggest that ultrasound is more sensitive than cell-free DNA (cfDNA) testing in screening for 22q11.2 deletion, citing a study by Schindewolf et al.2. However, that study was intended to document the ultrasound findings seen most frequently in pregnancies with a 22q11.2 deletion in the second and third trimesters, not to determine the sensitivity of ultrasound for fetal 22q11.2 deletion. To our knowledge, this has not been evaluated in any study. Nonetheless, we agree that prenatal ultrasound findings have been well described by Schindewolf et al. and others and suggest that cfDNA screening in the first trimester can complement, not replace, second-trimester ultrasound as a screening tool for 22q11.2 deletion. As Drs Jing and Li note, the collective prevalence of other fetal microduplications and microdeletions is not insignificant, even when ultrasound is normal, and there is broad consensus that chorionic villus sampling or amniocentesis with microarray analysis should be offered whenever evaluation of a pregnancy for submicroscopic genomic alterations is desired. Similar to Drs Jing and Li, we would also welcome a method for accurate, genome-wide non-invasive prenatal screening with demonstrated clinical utility for detecting chromosomal imbalances at a resolution comparable to that of microarray, but currently available technologies fall short of this goal. In a prospective head-to-head comparison of genome-wide cfDNA testing and chromosomal microarray testing in 198 pregnancies, Guseh and colleagues showed that expanded non-invasive genome-wide screening has a lower detection rate for clinically significant chromosomal abnormalities when compared with that of chromosomal microarray analysis, and that pathogenic subchromosomal imbalances (< 7 Mb) contribute substantially to the missed abnormalities3. A clinical trial from The Eunice Kennedy Shriver National Institute of Child Health and Human Development showed that > 50% of (likely) pathogenic subchromosomal imbalances identified by chromosomal microarray analysis in anatomically normal fetuses are < 5 Mb in size4. We would also like to clarify a minor point. The cfDNA test evaluated in our study is described as ‘targeted’ in order to differentiate it from ‘genome-wide’ cfDNA testing because of the different technological design of the two approaches. It is not a standalone test for 22q11.2 deletion, as might have been misinterpreted from the phrasing. The Harmony® test screens for trisomy 21, trisomy 18 and trisomy 13, with the option of screening for sex chromosome aneuploidy and/or 22q11.2 deletion from the same blood collection. In many respects, we agree with Drs Jing and Li and support an approach to prenatal screening in which the benefits of cfDNA testing, ultrasound and diagnostic testing are incorporated to guide pregnancy management and improve outcome in 22q11.2 deletion syndrome and other prenatally diagnosable conditions.