Validity and Utility of Non-Invasive Prenatal Testing for Copy Number Variations and Microdeletions: A Systematic Review

Abstract

Valid data on prenatal cell-free DNA-based screening tests for copy number variations and microdeletions are still insufficient. We aimed to compare different methodological approaches concerning the achieved diagnostic accuracy measurements and positive predictive values. For this systematic review, we searched the Scopus and PubMed databases and backward citations for studies published between 2013 and 4 February 2022 and included articles reporting the analytical and clinical performance of cfDNA screening tests for CNVs and microdeletions. Of the 1810 articles identified, 32 met the criteria. The reported sensitivity of the applied tests ranged from 20% to 100%, the specificity from 81.62% to 100%, and the PPV from 3% to 100% for cases with diagnostic or clinical follow-up information. No confirmatory analysis was available in the majority of cases with negative screening results, and, therefore, the NPVs could not be determined. NIPT for CNVs and microdeletions should be used with caution and any developments regarding new technologies should undergo strict evaluation before their implementation into clinical practice. Indications for testing should be in correlation with the application guidelines issued by international organizations in the field of prenatal diagnostics.

Non-Invasive Prenatal Testing in Germany

“…Overall, there are dozens of variants of NIPT available, but they are not really distinguished in the literature [ 18 , 21 ]. This combination issue, if applied to all studies using molecular cytogenetics/fluorescence in situ hybridization (FISH) in prenatal samples [ 22 ], would be as if they were all reported as similar results e.g., “invasive prenatal FISH testing” (IPFT), a misnomer, which would fail to distinguish whether the results were based on interphase or metaphase FISH, and/or which and how many different probes were applied.…”

BinDel: detecting clinically relevant fetal genomic microdeletions using low-coverage whole-genome sequencing-based NIPT

“…1:2,500 translates to that in a population of pregnant women younger than 35 years fetal microdeletions are more common than Down syndrome [2]. As there are no biomarker-based screening tests for MDs for first trimester screening (ultrasound sonography procedure can only sometimes detect associated findings for specific MD syndromes), a reliable NIPT-based microdeletion screening is required [4].…”

“…While pathogenic microdeletions are individually rare, with frequencies ranging from 1:1,524 for MD causing DiGeorge syndrome to 1:50,000 for MD causing Cri-du-chat syndrome, the overall prevalence rate of microdeletions is estimated to be approximately 1:2,500 [1][2][3].…”

“…While pathogenic microdeletions are individually rare, with frequencies ranging from 1:1,524 for MD causing DiGeorge syndrome to 1:50,000 for MD causing Cri-du-chat syndrome, the overall prevalence rate of microdeletions is estimated to be approximately 1:2,500 [1–3]. 1:2,500 translates to that in a population of pregnant women younger than 35 years fetal microdeletions are more common than Down syndrome [2]. As there are no biomarker-based screening tests for MDs for first trimester screening (ultrasound sonography procedure can only sometimes detect associated findings for specific MD syndromes), a reliable NIPT-based microdeletion screening is required [4].…”

“…While screening of pathogenic microdeletions in NIPT has been studied, a systematic review by Zaninović et al . notes that there is no consistency in achieved sensitivity, specificity, and PPV rates depending on the copy number variation (CNV) size between different studies [2]. Here we systematically investigated the importance of chromosomal region-specific characteristics with algorithm parameters in detecting microdeletions and exact connections between FF, coverage and different MD regions.…”