Expanding noninvasive prenatal testing to include microdeletions and segmental aneuploidy: cause for concern?

Abstract

Yatsenko et al., 1 "Maternal Cell-Free DNA-Based Screening for Fetal Microdeletion and the Importance of Careful Diagnostic Follow-Up, " describing a single prenatal case identified by noninvasive prenatal screening as harboring a deletion at 22q11.2. Upon diagnostic postnatal testing, however, a smaller, noncritical deletion at 22q11.21 was identified. As stated by the authors, noninvasive prenatal screening (also referred to as noninvasive prenatal testing (NIPT)) has emerged as a powerful tool in screening for fetal aneuploidies. Major providers of this technology have expanded their test offerings to include screening for common microdeletion syndromes. Despite high sensitivity and specificity for common trisomies, the recent literature suggests a need for extreme caution in interpreting NIPT because of false-positive rates higher than previously reported when compared with invasive testing as well as concerns regarding the potential for overrepresentation of the positive predictive value for specific aneuploidies. 1,2 We wanted to make an important and substantial addition to the observation by Yatsenko et al. 3 based on our analysis of cases evaluated by NIPT over the past year and subsequently referred to our laboratory for diagnostic testing by chromosomal microarrays and/or karyotype analysis. From our analysis of 287 consecutive samples, NIPT results were available for 278 cases, and diagnostic testing results were available for 277 of these cases. Of the 88 cases with normal NIPT results, diagnostic testing was concordant (normal chromosomal microarrays and/or karyotype) in 79 cases; discordant in 4 (2 cases with gender discordance, 1 case with monosomy X, and 1 case with two large duplications at 1q42.13q44 and 22q11.1q12.3); and concordant but with a structural variation in 5 cases (1 case with inversion 7, 3 cases with a small deletion or duplication, 1 case with a deletion and a duplication). For 162 cases with NIPT suggestive of a whole-chromosome aneuploidy, diagnostic testing was concordant in 69.8% cases, with the highest true-positive rate for trisomy 21 (88.4%) and the lowest for monosomy X (28%). Results were discordant in 23.5% of cases, with the highest discordant rates for trisomy 13 and monosomy X (47 and 72%, respectively). In 11 cases (6.7%), diagnostic testing revealed results that were only partially concordant with NIPT.The most significant and recent observation we wish to highlight in this letter is 25 cases for which NIPT results suggested a microdeletion or a segmental aneuploidy ( Table 1). The falsepositive rates were uniformly high for the common microdeletions tested for by some providers using expanded versions of NIPT. Notably, diagnostic testing revealed false-positive NIPT results in five of seven cases with 22q11.21 deletion, five of six cases with 5p deletion, three of four cases with 1p36 deletion, and one of one case with 4p deletion. Diagnostic testing results SAHOO et al | Expanding NIPT to include microdeletions and segmental aneuploidiesLetter to the editor wer...

False positive cell free DNA screening for microdeletions due to non‐pathogenic copy number variants

“…Similar to Case 1 here, their patient had a deletion downstream of the DiGeorge critical region that is present in <0.1% of the phenotypically normal population. A more recent report of a variety of non‐trisomic chromosomal anomalies reported by cfDNA has also described limited concordance with cytogenomic microarray . Here we report additional variants both in the 22q11 and 15q11 regions that suggest a general mechanism for false positive cfDNA testing.…”

Clinical experience of laboratory follow‐up with noninvasive prenatal testing using cell‐free DNA and positive microdeletion results in 349 cases

“…Sahoo et al followed up 19 cfDNA detected microdeletions (involving these 5 chromosomes) with diagnostic testing and found that only 5 could be confirmed with diagnostic testing. Most recently, Martin et al retrospectively analyzed the performance of SNP‐based NIPT in 80 449 fererrals for 22q11.2 deletion syndrome and 42 326 referrals for 1p36, cri‐du‐chat, Prader‐Willi, and Angelman microdeletion syndromes.…”

False negative fetal cell free DNA screening for microdeletion syndromes in the presence of an unbalanced translocation involving monosomy 4p

“…For various microdeletions, testing laboratories have reported analytical validation using cell‐line or spike‐in samples and indicated very high sensitivities and specificities of >96% . However, the frequency of false negative results is essentially unknown in real‐world applications using commercial assays . In fact, to our knowledge, prior to this case, false negative results from similar commercial assays have not been reported.…”