Clinical utility of trio whole exome sequencing in fetuses with ultrasound anomalies.

Introduction: Ultrasound scanning anomalies in fetuses are a cause for concern and often necessitate further diagnostic procedures. This retrospective study evaluated the utility of trio whole exome sequencing (trio-WES) in the diagnosis of fetuses with ultrasound anomalies.

Methods: We included fetuses diagnosed with fetal ultrasound anomalies referred to the First Affiliated Hospital of Chongqing Medical University between November 2018 and July 2023. Fetal anomalies were classified into structural anomalies, dynamic anomalies, and soft markers. Karyotype analysis, chromosomal microarray analysis (CMA) or copy number variation sequencing (CNV-seq) and trio-WES were performed for the eligible cases. Perinatal outcomes were recorded and evaluated at postnatal follow-up.

Results: A total of 316 fetuses were included for the analysis, including 199 (63.0%) cases with structural abnormalities, 63 (19.9%) cases with dynamic abnormalities, and 54 (17.1%) fetuses with ultrasonic soft markers. The diagnostic yield of karyotyping and CMA/CNV-seq was 4.1% (13/316), and Trio-WES achieved an additional diagnosis rate of 15.8% (50/316). Pathogenic or likely pathogenic alleles (P/LP) variants of 132 genes were identified in 125 (39.6%, 125/316) cases, and variant of uncertain significance (VUS) was detected in 81 samples (25.6%, 81/316). Ten cases (3.2%, 10/316,) were found to have pathogenic karyotype or CNVs in supplementary analysis of WES. Fetuses presenting musculoskeletal anomalies and multiple anomalies demonstrated highest diagnostic rates at 36.4% (8/22) and 36.1% (13/36), respectively. The diagnostic rate of fetuses with short femur was 20% (8/40), significantly higher than other ultrasonic soft markers. The modes of inheritance observed in patients with molecular diagnoses were autosomal dominant (AD) in 66.0% cases (33/50), autosomal recessive (AR) in 26.0% cases (13/50), and X-linked (XL) in 8.0% cases (4/50).

Conclusion: The integration of CMA/CNV-seq with trio-WES, alongside prenatal ultrasound scanning, holds the promise of significantly enriching our ability to decipher fetal phenotypes. This tripartite approach stands to revolutionize the diagnostic process, offering a more comprehensive and nuanced understanding of the underlying genetic architecture that underpins prenatal anomalies.