Breaking the 7 Mb barrier: Clinical cohort validation of genome-wide NIPT with fetal fraction enrichment and BinDel for detection of 1 Mb microdeletions and -duplications

Abstract

ObjectiveTo evaluate the analytical and clinical performance of fetal fraction (FF) enriched genome-wide noninvasive prenatal testing (GW-NIPT) for detection of clinically relevant copy number variants (CNVs) down to 1 Mb. MethodsWe retrospectively analyzed 10,501 singleton pregnancies tested with FF enrichment-based GW-NIPT between August 2023 and July 2025. CNV analysis was performed using BinDel and WisecondorX. ResultsFF enrichment increased median FF to 24% (2.4-fold increase). Clinically relevant CNVs, including microdeletions and microduplications, were reliably detected down to 1 Mb. Performance was robust across all maternal body mass index (BMI) categories. The retest rate was 0.95%, resulting in a final no-call rate of 0.03% with no BMI-attributable failures. The workflow demonstrated high sensitivity, specificity, and positive predictive value for common aneuploidies, rare autosomal trisomies, sex chromosome aneuploidies, subchromosomal CNVs, and pathogenic mitochondrial DNA variants. ConclusionsFF enrichment enhances the analytical resolution of first-trimester GW-NIPT, enabling reliable detection of subchromosomal CNVs down to 1 Mb across diverse patient populations. This approach broadens the scope of prenatal screening while maintaining low test failure rates. All positive findings require confirmatory diagnostic testing and appropriate genetic counseling.