Prenatal Exome Sequencing Analysis in Fetuses With Structural Anomalies: A Multicenter Prospective Cohort Study With...

Area of Science:

• Medical Genetics
• Prenatal Diagnostics
• Genomic Medicine

Background:

• Chromosomal microarray analysis (CMA) and karyotyping have limitations in diagnosing fetal structural anomalies.
• Exome sequencing (ES) offers a more comprehensive genetic analysis.
• Integrating copy number variant (CNV) and single nucleotide variant (SNV) analysis with ES (ES-CNV/SNV) can enhance diagnostic accuracy.

Purpose of the Study:

• To assess the diagnostic value of ES-CNV/SNV in fetuses with structural anomalies after negative standard genetic testing.
• To identify challenges in the clinical implementation of ES-CNV/SNV for prenatal diagnosis.
• To explore the utility of ES-CNV/SNV in detecting compound CNV/SNV combinations.

Main Methods:

• A multicenter prospective cohort study involving 275 fetuses with structural anomalies.
• Trio-based ES-CNV/SNV analysis to detect single nucleotide variants (SNVs), copy number variants (CNVs), and compound heterozygous CNV/SNV combinations.
• Categorization of fetuses into sporadic single-system, sporadic multisystem, and recurrent anomaly groups.

Main Results:

• ES-CNV/SNV analysis achieved a diagnostic yield of 29.45% (81/275), surpassing conventional methods.
• The highest diagnostic yield was in the recurrent anomaly group (40.68%), followed by multisystem (28.41%) and single-system (25.00%) groups.
• Compound CNV/SNV combinations were identified in 1.45% of cases, highlighting potential for diagnosing autosomal recessive disorders.

Conclusions:

• ES-CNV/SNV significantly enhances prenatal diagnostic precision for fetal structural anomalies.
• This method is particularly valuable for high-risk cases, such as those with recurrent anomalies.
• The study expands understanding of prenatal phenotypic-genotypic correlations and developmental mechanisms.