Low-Pass Genome Sequencing Reveals Associations Between Chromosomal Aberrations and Ultrasonographic Anomalies in a Cohort of 19,452 Fetuses.

OBJECTIVE

This study aimed to evaluate the detection rates of aneuploidies and pathogenic/likely pathogenic copy number variations (pCNV) using low-pass genome sequencing (LP-GS), also known as CNV-seq, across different ultrasonographic anomalies and to systematically elucidate the associations between specific types of chromosomal aberrations and specific ultrasonographic anomalies.

METHOD: LP-GS was performed in 19,452 fetuses, including those with ultrasonographic anomalies (n = 13,312) and those with normal ultrasonography (n = 6140). The detection rates of pCNV among fetuses with various ultrasonographic anomalies were compared with those of fetuses with no identifiable anomalies. In addition, the associations between ultrasonographic anomalies and aneuploidies or pCNV were investigated using Fisher's exact test.

RESULTS

The detection rates of aneuploidies and pCNV were 6.20% (825/13,312) and 6.19% (824/13,312), respectively, in fetuses with ultrasonographic anomalies. Fetal hydrops was the ultrasonographic anomaly with the highest diagnostic rate for aneuploidies, at 32.58% among all isolated groups, particularly when combined with cystic hygroma, for which the diagnostic rate was 61.04%. Ten types of isolated ultrasonographic anomalies showed significantly higher diagnostic rates of pCNV (3.90%-7.43%, p < 0.05, odds ratio = 2.19-4.32). Furthermore, this study first reported an association between 3q25.2-q29 duplication and abdominal wall defects.

CONCLUSIONS

Our findings expanded the phenotypic spectrum of certain pCNVs and highlighted phenotype-specific differences in the diagnostic yield of LP-GS, providing valuable reference information for genetic counseling in prenatal diagnosis.