The added value of whole-exome sequencing for fetuses with postural defects by prenatal ultrasound

To investigate the genetic etiology of fetal postural anomalies using whole-exome sequencing (WES) and elucidate the genotype-phenotype correlation between prenatal sonographic findings and molecular signatures.

A retrospective single-center cohort study was conducted at the Center of Medical Genetics, Hubei Maternal and Child Health Hospital between September 2020 and August 2025. The study enrolled 100 fetuses with prenatal ultrasound-confirmed postural anomalies, including fixed abnormal hand positioning, persistent limb contractures, clubfeet, or lower-limb deformities. All cases first underwent chromosomal microarray analysis (CMA) or copy-number variation sequencing (CNV-seq). WES was subsequently performed on fetuses with normal CMA/ CNV-seq results.

Among the 100 fetuses, 12 (12.0%, 95% confidence interval [CI]: 6.4%-20.0%) pathogenic chromosomal abnormalities were identified by CMA/CNV-seq. WES was performed on the remaining 88 fetuses, yielding a molecular diagnosis in 17 (19.3%, 95% CI: 11.7%-29.1%) cases. The combined sequential testing strategy (CMA/CNV-seq followed by WES) achieved an overall diagnostic yield of 29.0% (95% CI: 20.4%-38.9%). Notably, no monogenic pathogenic variants were identified in fetuses with truly isolated postural anomalies; the diagnostic yield was significantly higher in cases with additional limb or extra-skeletal malformations. The 17 positive cases involved 26 distinct variants across 16 genes, with recurrent variants in FGFR2 and NEK1 (two cases each). While SOX9 is frequently implicated in other cohorts, it was absent in our study; instead, COL1A1 and DYNC2H1 emerged as the most frequently shared genes.

WES provides a substantial incremental yield (19.3%, 95% CI: 11.7%-29.1%) in fetuses with negative results on CMA/CNV-seq. WES should be prioritized for fetuses with postural anomalies co-occurring with extra-skeletal defects, as isolated postural anomalies demonstrate a negligible monogenic risk. Our findings expand the genetic spectrum of fetal postural anomalies and inform precision genetic counseling and obstetric management, emphasizing phenotype-driven testing algorithms.