Caution urged in interpreting NIPS microdeletion results

see Maternal cell-free DNA–based screening for fetal microdeletion and the importance of careful diagnostic follow-up

Noninvasive prenatal screening (NIPS) is often seen as a relatively low-risk screening test that can identify chromosomal abnormalities early in pregnancy. Although NIPS has established itself as a useful tool for identifying fetal trisomies, the real-world consequences of adding screening for smaller chromosomal microdeletions have not been rigorously evaluated. In this issue, Yatsenko et al. offer a cautionary report involving a false-positive NIPS result in the DiGeorge syndrome region (22q11.2). The report describes the case of a 40-year-old pregnant woman who underwent NIPS due to advanced maternal age. A commercially available NIPS test returned a positive result for a 22q11.2 microdeletion but did not pinpoint its exact chromosomal coordinates. The patient declined further diagnostic testing and delivered a healthy infant at 32 weeks gestation. After the birth, microarray analysis on mother and child revealed a microdeletion of unknown significance that did not include the gene associated with classic DiGeorge syndrome, a genetic defect that affects about one in 4,000 births. Because the accuracy of NIPS microdeletion detection is still unknown, the authors suggest that its commercial use is premature. However, if offered, any positive screening result should trigger further diagnostic testing of the fetus and both parents, if possible. The authors further argue that exact genomic coordinates of any abnormality should be reported. In the case described here, knowing the precise location and extent of the microdeletion would have been valuable to both the patient and the physicians charged with her care. —Karyn Hede, News Editor

New model shows genetic risk factors could help personalize prostate cancer screening

see Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis

The value of screening men over 50 for prostate-specific antigen (PSA) has been thoroughly refuted in several large epidemiological studies showing that the risks of overdiagnosis and treatment outweigh the test’s potential benefits. But some researchers haven’t given up on the PSA screening test. In this issue, Pashayan and colleagues describe a mathematical model that combines data from several large United Kingdom–based prostate cancer trials with 66 genetic markers associated with prostate cancer risk in European populations. Dividing the data into quartiles by risk, they calculated that in the lowest-risk group 43% of screening-detected cases were likely to be overdiagnosed, while in the highest-risk group 19% were likely to be overdiagnosed. The proportion of overdiagnosed cases was 56% lower in the highest-risk group than in the lowest-risk group. They conclude that targeting screening to men at higher genetic risk could reduce the number of men likely to be overdiagnosed. However, the research is limited by assumptions made for test sensitivity and tumor behavior, which may be influenced by genetic background in ways that are not yet understood, and more study is clearly warranted before using this type of analysis clinically. Finally, while personalized screening sounds good, public reaction to recommended changes in screening frequency can be volatile, as evidenced by the controversy over proposed changes in mammography screening. —Karyn Hede, News Editor