Increased Positive Predictive Value for a Single-Nucleotide Polymorphism-Based Non-invasive Prenatal Test for the 22q11.2 Deletion

Abstract Non-invasive prenatal testing (NIPT) has expanded its coverage beyond the common aneuploidies to include subchromosomal abnormalities such as the 22q11.2 deletion through the analysis of cell-free DNA. We previously reported a positive predictive value (PPV) of 18% and false-positive rate (FPR) of 0.38% for a single-nucleotide polymorphism (SNP)-based NIPT for fetal 22q11.2 deletion in a clinical cohort. Herein, we assess the performance of the test following methodology changes that include sequencing high-risk calls at high depth of read (HDOR) and raising the confidence threshold of the algorithm from 0.90 to 0.95. At the original confidence cut-off, a PPV of 42.3% upon reflex-sequencing of high-risk samples at a HDOR was reported. Raising the algorithm’s confidence threshold further increased the PPV to 52.4% and reduced the FPR to 0.07%, with no loss in test sensitivity. The PPV was 100% for high a priori risk cases, and 20% for low a priori risk cases. The improved assay performance documented with the updated methodology supports the efficacy of the SNP-based NIPT in the detection of fetal 22q11.2 deletion.