22q11.2 microdeletions are more common than trisomies 18 and 13 combined, but no routine approach to prenatal screening has been established. This study evaluates the clinical sensitivity and specificity of a targeted cfDNA test to screen for fetal 22q11.2 deletions in a large cohort through blinded analysis of prospectively enrolled pregnancies and collected clinical samples.
In order to analyze a meaningful number of cases with a 22q11.2 deletion, samples were obtained through a prospective, multicenter enrollment of pregnancies with fetal cardiac abnormalities and collection of clinical samples from a research sample bank. Fetal genetic status as evaluated by microarray analysis, karyotype with FISH, or comparable technology was available for every case enrolled. Samples were processed as previously described for the Harmony prenatal test with the addition of DANSR (Digital Analysis of Selected Regions) assays targeting the 3.0Mb region of 22q11.2. Operators were blinded to genetic truth. Sensitivity and specificity of the cfDNA test for 22q11.2 deletions were calculated based on concordance between the cfDNA result and fetal genotype.
The final study group consisted of 735 clinical samples: 358 prospectively enrolled pregnancies and 377 collected clinical samples. Of 46 maternal plasma samples from pregnancies with a 22q11.2 deletion ranging in size from 1.25 to 3.25 Mb, 32 had a cfDNA result indicating a high probability of deletion (sensitivity 69.6%; 95% CI: 55.2-80.9%). All 689 maternal plasmas without 22q11.2 deletions were correctly classified to have no evidence of a 22q11.2 deletion by cfDNA analysis, a specificity of 100% (95% CI: 99.5-100).
This is a large-scale prospective clinical evaluation of the sensitivity and specificity of a targeted cfDNA test for fetal 22q11.2 deletions. Results demonstrate that this targeted cfDNA test can detect common and smaller, nested 22q11.2 deletions with a low (0-0.5%) false positive rate. Although the PPV observed in this study population was 100%, the expected PPV in the general pregnancy population can be calculated as 12.2% using 99.5% specificity and 41.1% at 99.9% specificity. Use of this cfDNA test to screen for 22q11.2 deletions could enhance identification of pregnancies at-risk for 22q11.2 deletion syndrome without significantly increasing the likelihood of maternal anxiety and unnecessary invasive procedures related to false positive results. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.
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