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Fetal structural anomalies are associated with whole chromosome aneuploidy and sub-chromosomal copy number variants (CNVs) in approximately 3-6% of cases. Although the recommended evaluation of a fetus with an anomaly is diagnostic testing with microarray analysis, many physicians are offering non-invasive prenatal testing (NIPT) in cases where patients wish to avoid an invasive diagnostic procedure. This analysis evaluates the hypothetical performance of NIPT in this scenario.
This is a secondary analysis of 2 NICHD funded prospective studies evaluating the frequency of aneuploidy and CNVs diagnosed in utero. We determined the frequency of cytogenetic abnormalities in fetuses with structural anomalies (including NT ≥3.5mm). We calculated the ability of either single nucleotide polymorphism (SNP) based NIPT or massively parallel sequencing (MPS) based NIPT to identify these abnormalities. We assumed that SNP-based NIPT could identify all cases of trisomies 13, 18, 21, sex chromosome abnormalities, triploidy and deletions of 1p36, 4p, 15q11, and 22q11.2. MPS-based expanded NIPT was assumed to detect all trisomies and CNVs ≥7Mb as well as deletions of 1p36, 4p, 5p, 8q24, 11q23, 15q11.2, 17p11.2, and 22q11.2.
There were 1,724 fetuses with structural anomalies, 317 (18.4%) of which had an abnormal karyotype, and 106 (3.5%) of which had a pathogenic CNV. Among these, 1,294 had an isolated structural anomaly and 430 had multiple anomalies. Table 1 shows the cytogenetic abnormalities. SNP-based NIPT would identify 79.1% of the abnormalities and MPS-based would identify 87.4%. Detection rates vary by specific organ system, as shown in Table 2.
An expanded MPS-based and a SNP-based NIPT could potentially identify 87.4% and 79.1%, respecitively, of cytogenetic abnormalities among fetuses with structural anomalies. However, this assumes that NIPT has 100% detection of all intended anomalies. Accordingly, its detection in clinical practice will be less. Patients choosing NIPT as their primary genetic test for a structural abnormality must be informed of his limitations.