Enhanced genetic diagnosis in early pregnancy loss: an integrated approach using CNV-Seq and STR genotyping

Chromosomal abnormalities are a leading cause of early pregnancy loss (EPL). While copy number variation sequencing (CNV-seq) is gradually applied in clinical practice, its sensitivity for detecting triploidy and uniparental disomy (UPD) remains limited. This study aimed to evaluate whether integrating CNV-seq with short tandem repeat (STR) genotyping could improve diagnostic performance in EPL.

In this study, 572 EPL samples were examined using CNV-seq combined with STR genotyping to detect chromosomal abnormalities, including triploidy and UPD, and to explore STR-based approaches for identifying the origin of abnormal chromosomes. Selected results were validated using karyotyping, CMA, MLPA, or FISH when necessary.

Chromosomal abnormalities were identified in 313 cases (54.7%), including autosomal aneuploidies (52.4%), CNVs (13.4%), sex chromosome aneuploidies (11.5%), multiple trisomies (3.5%), and mosaicism (3.5%). STR genotyping identified 38 additional cases (35 triploidy, 3 UPD) missed by CNV-seq, elevating the overall diagnostic yield by 6.6% (p < 0.05). Parental origin analysis revealed distinct distribution patterns: 69,XXY triploidies were predominantly of paternal origin (80.8%), whereas 69,XXX cases were mostly maternal (88.9%); all detected UPD cases were paternally derived. Among 134 common autosomal aneuploidies, maternal meiotic errors accounted for 91.8% of occurrences.

The combination of CNV-seq and STR genotyping significantly improves the detection efficiency of triploidy, mosaicism, and other complex chromosomal anomalies, compensating for crucial limitations of conventional CNV-seq. Further STR-based parental tracing facilitates the identification of chromosomal aberration origins and reveals error formation patterns, thereby providing robust evidence for clinical etiological interpretation of early pregnancy loss.