Validation of low-pass genome sequencing for prenatal diagnosis

ObjectiveChromosomal microarray (CMA), while considered the gold standard for detecting copy number variants (CNVs) in prenatal diagnostics, has its limitations, including the necessity to replace aging microarray equipment, low throughput, a static design, and an inefficient multi-day workflow. This study evaluates the feasibility of low-pass genome sequencing (LP-GS) as a potential replacement for CMA in prenatal diagnostics.MethodsWe comprehensively compared LP-GS at 10x and 5x average depths with CMA in a prenatal laboratory. We examined parameters, including concordance, sensitivity, specificity, workflow efficiency, and cost-effectiveness.ResultsWe found a high degree of agreement between LP-GS and CMA for detecting CNVs and absence of heterozygosity. Furthermore, compared to CMA, LP-GS increased workflow efficiency and proved to be cost-neutral at 10x and cost-effective at 5x.ConclusionOur study suggests that LP-GS is a promising alternative to CMA in prenatal diagnostics, offering advantages, including a more efficient workflow and scalability for larger testing volumes. Importantly, for clinical laboratories that have adopted next-generation sequencing in a separate capacity, LP-GS facilitates a unified NGS-centric approach, enabling workflow consolidation. By offering a single, streamlined platform for detecting a broad range of genetic variants, LP-GS may represent a critical step toward enhancing the diagnostic capabilities of prenatal laboratories. What's already known about this topic?Chromosomal microarray (CMA) is currently the gold standard for analyzing copy number variants (CNVs) in prenatal diagnostics.However, CMA is limited by relatively low throughput, inefficient workflow, and a static test design that does not easily accommodate updates or novel disease associations.With more laboratories transitioning to next-generation sequencing (NGS), there is a growing need for a unified workflow to streamline diagnostic procedures.Low-pass genome sequencing (LP-GS) is emerging as an alternative to CMA for CNV detection.What does this study add?Our study assessed the potential of LP-GS to replace CMA in our prenatal laboratory setting.We systematically compared the performance of LP-GS at 10x and 5x average depths to CMA and found excellent concordance, sensitivity, and specificity.LP-GS has a streamlined and efficient workflow compared to CMA and offers economic benefits of being cost-neutral at 10x and cost-effective at 5x average read depths.Our findings indicate that LP-GS is a potential alternative to CMA in prenatal diagnostics addressing some of the existing constraints in the field, including the shortage of genetic technologists.