Clinical Edge Journal Scan

Clinical Edge Journal Scan Commentary: Prenatal Testing March 2022

Dr. Longman scans the journals, so you don’t have to!

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Ryan Longman, MD

A common group of brain malformations found in fetuses are callosal abnormalities (CA). A recent study by Lei et al in the journal Prenatal Diagnosis investigated the value of using exome sequencing (ES) in fetuses with CA to determine the likelihood of detecting a causative genetic variant. They performed ES (fetus-parental trios) on fetuses that had CA with or without other structural anomalies. All studied fetuses had normal karyotypes (KT) and chromosomal microarray (CMA) testing. Of the 50 fetus-parental trios analyzed, 34% (17/50) had a diagnostic genetic variant, of which 29.4% (10/35) were isolated and 43.8% (7/15) had other structural anomalies. This study shows the importance of using ES in making a prenatal genetic diagnosis for fetuses with CA when KT and CMA are normal.

Many neurocognitive disorders only present a phenotype after birth. Sukenik-Halevy et al sought to examine the ability to detect prenatal phenotypes in patients with a postnatally diagnosed neurocognitive syndrome and confirmed genetic diagnosis on ES. The team was not able to identify any specific prenatal phenotype associated with their cases of postnatally diagnosed neurocognitive syndromes. The interesting finding of this study is that, of the 122 patients studied, 35.3% (43) had no abnormal sonographic findings that could have been detected prenatally to suggest the need for ES testing. ES is typically used in a prenatal setting for fetuses with anomalies that have a normal KT and CMA. The results of this study raise the question of offering ES to all patients considering diagnostic genetic testing regardless of the indication, as it may be the only way to diagnose some cases of neurocognitive disorders prenatally.

Cell-free fetal DNA (cff DNA) testing for trisomy 21, 18, and 13 has classically be used for high-risk pregnant patients seeking aneuploidy screening. Dar et al sought to examine this type of testing in a low-risk population. They studied, prospectively, the performance of cff DNA testing for trisomy 21, 18, and 13 in both low and high-risk pregnant women with confirmation of results on diagnostic genetic testing. Negative predictive values (NPV) for both the low and high-risk groups were greater than 99.9%. Positive predictive value (PPV) was lower for the low-risk group in comparison to the high-risk group, with it important to note that PPV drops from 96.4% in the high-risk group to 81.8% in the low-risk group for trisomy 21. This means that low-risk patients with a positive result on cff DNA testing are at a higher risk for a false positive than patients at high-risk for an aneuploid fetus. This study shows the mounting evidence that cff DNA can be used in a low-risk population given the high NPV. Providers do still need to note the lower PPV with low-risk population patients and always offer diagnostic genetic testing with any abnormal cff DNA test result.

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