Recurrent pregnancy loss (RPL) remains one of the most challenging conditions in reproductive medicine, affecting approximately 1–2% of couples worldwide. Among all etiologies, chromosomal abnormalities in the embryo, including aneuploidies, structural rearrangements, and pathogenic copy number variations (CNVs), constitute the largest identifiable cause, particularly during the first trimester, when over 80% of miscarriages occur. Chromosomal abnormalities contribute to up to 50–60% of early losses.

Advances in Next-Generation Sequencing (NGS) have enabled the use of Copy Number Variation Sequencing (CNV-seq), a high-resolution, high-throughput whole-genome method that overcomes the limitations of conventional cytogenetic techniques. CNV-seq provides a more accurate, sensitive, and efficient diagnostic approach for evaluating miscarriage tissue and understanding the genetic basis of recurrent miscarriage.

The Role of Chromosomal Abnormalities in Recurrent Miscarriage

Large cohort studies show that 61.1% of tissues from early miscarriages harbor chromosomal abnormalities, with aneuploidy being the predominant cause. Among pathogenic CNVs detected in miscarriage tissue, greater than 1 Mb account for 88–93% of cases, whereas smaller CNVs (less than 1 Mb) account for 7–12%.

These abnormalities often arise de novo during gametogenesis or early embryogenesis and cannot be predicted by parental karyotyping alone. Therefore, testing the tissue from a miscarriage is clinically indispensable.

International guidelines, including those from the American Society of Reproductive Medicine (ASRM), European Society of Human Reproduction and Embryology (ESHRE), and Royal College of Obstetricians and Gynaecologists (RCOG), recommend chromosomal analysis of miscarriage tissue as a core component of recurrent pregnancy loss (RPL) evaluation.

Limitations of Conventional Testing for Miscarriage Tissue

Conventional karyotyping has several limitations that significantly reduce its reliability for miscarriage analysis. Because the method requires viable cell culture, many samples fail due to poor tissue viability, resulting in a high proportion of inconclusive results. Meta-analysis of 13 studies (7012 samples) shows an average karyotype success rate of only ~79%, primarily due to failed cell culture.

The long culture time, which often takes two to four weeks, further delays diagnosis and prolongs uncertainty for patients. Additionally, the risk of maternal cell contamination can lead to false-normal results, masking the embryo’s true chromosomal abnormalities. Even when successful, the technique’s low resolution of approximately 5–10 megabase pairs (Mb) prevents it from detecting clinically significant microdeletions and microduplications, which limits its ability to identify the genetic causes of miscarriage.

CNV-seq Solutions for Recurrent Miscarriage Diagnosis

A new technology, CNV-seq, uses low-pass whole genome sequencing (low-pass WGS) to detect copy number gains and losses across the entire genome. CNV-seq identifies abnormalities in up to ≥60% of miscarriage samples, significantly higher than karyotyping. It detects aneuploidies, segmental duplications/deletions, microdeletions/duplications missed by karyotype and triploidy (≈11.5% of chromosomal abnormalities).

CNV-seq does not depend on cell viability, eliminating culture failure. Based on the clinical advantage, CNV-seq has a faster turnaround time (7–14 days), higher detection resolution, CNV-seq detects chromosomal changes as small as 100 kb, compared to 5–10 Mb for karyotyping.

CNV-seq is able to identify pathogenic microdeletions/duplications, clinically relevant CNVs associated with neurodevelopmental disorders, congenital anomalies and embryonic lethality.

This test combined with genetic counseling can support clinical decision making with a high diagnostic yield, that can confirm genetic etiology of miscarriage, stratify recurrence risk, identify parental carriers, guide preconception planning, and inform PGT-A/M recommendations for future pregnancies.

Why CNV-seq Should Be the First-Line Test for Miscarriage Tissue?

Given the increasing availability of low-pass WGS, CNV-seq is emerging as the standard clinical method for analyzing miscarriage and recurrent miscarriage cases with several advantages:

1. Highest diagnostic yield among existing technologies
2. Guideline-aligned (ASRM/ESHRE/RCOG recommend chromosomal testing on POC tissue)
3. Comprehensive testing with high resolution detection up to 100 Kb
4. Cost-effective compared to CMA and karyotyping
5. Solid database from BGI

With the increasing need for precise and reliable genetic evaluation in recurrent miscarriage, the availability of advanced technologies plays a critical role in improving clinical decision-making. To support clinicians and patients with more accurate answers, NGI is now providing CNV-seq as a newly launched diagnostic solution. This genome-wide and high-resolution approach enables comprehensive detection of aneuploidies and pathogenic CNVs. We offer a higher diagnostic yield and more meaningful insights than conventional methods.

NALEYA CNV-seq service is designed to enhance the diagnostic workflow, strengthen genetic counseling, and help couples receive clearer guidance for future reproductive planning. For healthcare professionals seeking a more advanced and dependable tool for miscarriage evaluation, CNV-seq is now accessible through NGI as part of our commitment to elevating genomic medicine in Indonesia.

References:

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