Severity-stratified genetic diagnosis by trio exome sequencing in isolated fetal growth restriction.

Exome sequencing (ES) is increasingly used in prenatal diagnosis. However, its efficacy for isolated fetal growth restriction (FGR), especially across different levels of severity, is not well established. This study sought to evaluate and compare the diagnostic yield and clinical impact of trio-ES between isolated non-severe and severe FGR cases. In this retrospective study, 164 singleton pregnancies with isolated FGR were stratified into non-severe FGR (estimated fetal weight [EFW] between the third and 10th percentiles) and severe FGR (EFW <third percentile). All cases underwent chromosomal karyotyping and copy number variation sequencing. In parallel, trio-ES was performed in 125 cases. The diagnostic yield of trio-ES was then compared between the severity groups. Pathogenic or likely pathogenic (P/LP) variants were identified via trio-ES in 8.3% (3/36) of non-severe FGR cases and 18.0% (16/89) of severe FGR cases. In the non-severe group, all detected P/LP variants were associated with high-risk phenotypes and led to termination of pregnancy. In the severe group, these variants were associated with moderate-to-severe disorders, and pregnancy outcomes were diverse (50% termination). Furthermore, the severe FGR cohort exhibited a higher prevalence of preeclampsia and abnormal umbilical artery Doppler waveforms compared to the non-severe group, with adverse outcomes attributable to both monogenic disorders and maternal-placental factors. This stratified analysis demonstrates that ES provides substantial diagnostic value across the entire severity spectrum of isolated FGR, identifying clinically significant monogenic disorders in both severe and non-severe cases. These findings support the inclusion of ES in the diagnostic workup of isolated FGR, regardless of strict severity cut-offs. They also highlight the need for integrated genetic counseling to manage variants of uncertain significance and multifactorial risks, particularly in severe cases.