Clinical Validation of a Non-Invasive Prenatal Test for Genome-Wide Detection of Fetal Copy Number Variants

Background Current cell-free DNA (cfDNA) assessment of fetal chromosomes does not analyze and report on all chromosomes. Hence, a significant proportion of fetal chromosomal abnormalities are not detectable by current non-invasive methods. Here we report the clinical validation of a novel NIPT designed to detect genome-wide gains and losses of chromosomal material ≥7 Mb and losses associated with specific deletions <7 Mb. Objective The objective of this study is to provide a clinical validation of the sensitivity and specificity of a novel NIPT for detection of genome-wide abnormalities. Study Design This retrospective, blinded study included maternal plasma collected from 1222 study subjects with pregnancies at increased risk for fetal chromosomal abnormalities that were assessed for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), fetal sex, genome-wide copy number variants (CNVs) 7 Mb and larger, and select deletions smaller than 7 Mb. Performance was assessed by comparing test results with findings from G-band karyotyping, microarray data, or high coverage sequencing. Results Clinical sensitivity within this study was determined to be 100% for T21, T18, T13, and SCAs, and 97.7% for genome-wide CNVs. Clinical specificity within this study was determined to be 100% for T21, T18, and T13, and 99.9% for SCAs and CNVs. Fetal sex classification had an accuracy of 99.6%. Conclusion This study has demonstrated that genome-wide non-invasive prenatal testing (NIPT) for fetal chromosomal abnormalities can provide high resolution, sensitive, and specific detection of a wide range of sub-chromosomal and whole chromosomal abnormalities that were previously only detectable by invasive karyotype analysis. In some instances, this NIPT also provided additional clarification about the origin of genetic material that had not been identified by invasive karyotype analysis.