Chromosomal abnormalities are among the most significant contributors to fetal structural anomalies, developmental disorders, and adverse pregnancy outcomes. Conventional prenatal diagnostic technologies, primarily karyotyping and chromosomal microarray (CMA) have played central roles in clinical genetics, yet both are limited in their ability to detect the full spectrum of fetal genomic alterations. Increasing evidence from international research demonstrates that clinically significant copy number variations (CNVs) are often present even in fetuses with normal karyotype but abnormal ultrasound findings. In a cohort of 4,282 fetuses with ultrasound abnormalities but normal karyotype, it revealed an additional 6% of pathogenic microdeletions and microduplications that would have been missed by karyotyping alone.
More broadly, more than 300 known microdeletion and microduplication syndromes have been documented, collectively occurring at a combined frequency of approximately 1 in 600 pregnancies. These pathogenic CNVs account for nearly half of chromosome-related congenital anomalies, underscoring the necessity of genome-wide analysis during prenatal evaluation.
Professional societies have echoed these findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend that CMA or genome-wide sequencing-based methods be offered to patients undergoing invasive prenatal testing, because relying solely on karyotyping risks missing approximately 2.5% of clinically significant CNVs in high-risk pregnancies.
The International Society for Prenatal Diagnosis (ISPD) similarly emphasizes genome-wide technologies as the preferred approach for identifying submicroscopic chromosomal abnormalities in fetuses with structural anomalies.
CNV-seq as A New Generation Genome-Wide Diagnostic Tool
CNV-seq (Copy Number Variation Sequencing) applies low-pass whole genome sequencing, enabling comprehensive coverage across the entire fetal genome. Unlike CMA, which depends on fixed probe design, CNV-seq sequences all genomic regions with equal opportunity for detection, including areas where CMA has sparse probe coverage.
This advantage has been demonstrated clinically. In head-to-head comparison studies of prenatal samples, written in paper entitled Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis published in Nature Genetics in Medicine, shows that CNV-seq has a strong detection rate compared to CMA, with the full result comparison:
- CMA detected 121 pathogenic/likely pathogenic CNVs. CNV-seq detected 17 additional pathogenic CNVs missed by CMA, largely because the corresponding genomic regions lacked adequate probe density.
- CNV-seq also identified 6 additional VUS (Variants of Uncertain Significance) cases, including one case confirming Turner syndrome mosaicism.
- The initial experiment failure rate of CNV-seq was significantly lower: 0.5% vs. 4.6% for CMA, attributed to CNV-seq’s far lower DNA input requirement (50 ng vs. 200 ng).
These results reinforce CNV-seq’s practical and analytical superiority, especially in prenatal settings where sample quantity and quality may be limiting.
Clinical Advantages of CNV-seq Over Traditional Technologies
CNV-seq offers higher sensitivity and a significantly broader detection range compared with conventional prenatal diagnostic technologies. It is capable of identifying whole-chromosome aneuploidies as well as segmental copy number variations as small as approximately 100 kb. This includes the detection of clinically important microdeletion and microduplication syndromes, low-level mosaicism at around 10%, that may be missed by karyotyping or CMA.
Accurately identifying low-level mosaicism is vital in prenatal diagnosis because mosaic chromosomal anomalies can influence prognosis, recurrence risk, and genetic counseling. CNV-seq reliably detects as low as 10% mosaic fractions, substantially outperforming karyotype and CMA.
Its comprehensive genome-wide coverage makes CNV-seq particularly valuable for uncovering pathogenic CNVs linked to congenital heart disease, brain malformations, skeletal abnormalities, neurodevelopmental disorders, and various syndromic conditions, providing clinicians with a more complete and clinically actionable view of fetal genomic health.
Unlike karyotyping, CNV-seq does not require cell culture and is not affected by culture failure or maternal cell overgrowth. Compared with CMA, CNV-seq needs significantly less DNA, uses streamlined workflows, and has stronger performance in prenatal samples where fetal cell quantity may be limited.
CNV-seq offers faster processing, often within 10-14 days, facilitating timely counseling and clinical decision-making, particularly in pregnancies presenting with critical structural findings.
Conclusion
As prenatal genomics advances, the limitations of traditional technologies become increasingly evident. Karyotyping lacks the resolution to detect microdeletions and microduplications, while CMA is constrained by probe design and requires larger DNA input. CNV-seq, by contrast, delivers a comprehensive, sensitive, and clinically robust genome-wide assessment, capturing critical chromosomal abnormalities that would otherwise go undetected.
With strong support from clinical research, international guidelines, and real-world performance data, CNV-seq is rapidly emerging as a next-generation standard for prenatal diagnosis, offering clinicians and families deeper insight, greater diagnostic clarity, and improved confidence in pregnancy management decisions.
With the growing need for more comprehensive and sensitive prenatal diagnostics, the availability of advanced genomic tools is becoming essential in clinical care. To support clinicians in delivering clearer, more accurate fetal genomic assessments, NGI is now providing NALEYA CNV-seq as our newly launched genomic testing solution. This technology expands the diagnostic capabilities beyond what conventional methods can offer and is clinically applicable for evaluating chromosomal abnormalities in prenatal samples.
Designed to enhance diagnostic confidence, NALEYA CNV-seq enables genome-wide detection of aneuploidies and pathogenic CNVs with higher resolution and improved sensitivity, helping clinicians better interpret ultrasound findings, guide patient counseling, and inform pregnancy management. For healthcare professionals seeking a reliable and advanced approach to prenatal diagnosis, NALEYA CNV-seq service is now available as part of our commitment to advancing reproductive genetics in Indonesia.
References:
- Wang, H., Dong, Z., Zhang, R. et al. Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis. Genet Med 22, 500–510 (2020). https://doi.org/10.1038/s41436-019-0634-7
- Wapner, R. J., Martin, C. L., Levy, B., Ballif, B. C., Eng, C. M., Zachary, J. M., Savage, M., Platt, L. D., Saltzman, D., Grobman, W. A., Klugman, S., Scholl, T., Simpson, J. L., McCall, K., Aggarwal, V. S., Bunke, B., Nahum, O., Patel, A., Lamb, A. N., Thom, E. A., … Jackson, L. (2012). Chromosomal microarray versus karyotyping for prenatal diagnosis. The New England journal of medicine, 367(23), 2175–2184. https://doi.org/10.1056/NEJMoa1203382
- Hay, S. B., Sahoo, T., Travis, M. K., Hovanes, K., Dzidic, N., Doherty, C., & Strecker, M. N. (2018). ACOG and SMFM guidelines for prenatal diagnosis: Is karyotyping really sufficient?. Prenatal diagnosis, 38(3), 184–189. https://doi.org/10.1002/pd.5212
