Our recent study entitled, “Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes” by Wapner et al, demonstrated that single-nucleotide polymorphism-based noninvasive prenatal testing had high sensitivity and specificity for the detection of the 22q11.2 deletion. Since then, we have investigated whether resequencing samples that received a high-risk call at the standard depth of read (DOR) at a higher DOR (HDOR) would reduce the false-positive rate (FPR) and hence increase the positive predictive value (PPV) while maintaining high sensitivity.
In our original study, 45 22q11.2 deletion samples and 3 unaffected euploid samples received a high-risk result for a deletion in the 22q11.2 region at our standard DOR (average, 8.9 × 10 6 mapped reads). When these 48 samples were resequenced at a higher DOR (average, 17.2 × 10 6 mapped reads), all 45 true-positive samples were still classified as high risk. However, of the 3 unaffected samples that had been falsely called high risk at the standard DOR, 1 remained high risk, 1 received a low-risk call, and 1 received a no-call.
An additional 203 unaffected euploid samples called low risk at standard DOR were also run at HDOR. Of those, 195 received a low-risk call and 8 were not called by the algorithm; none received a high-risk call. At the standard DOR, the FPR for 22q11.2 deletion syndrome was reported as 0.76% (3 of 397) ; resequencing high-risk samples at HDOR reduced the FPR for 22q11.2 deletion syndrome to 0.25% (1 of 396), resulting in an increase in the PPV from 5.3% to 14.4% ( Table 1 ).
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