ORIGINAL RESEARCH article
Front. Genet.
Sec. Human and Medical Genomics
Severity-stratified genetic diagnosis by trio exome sequencing in isolated fetal growth restriction
Provisionally accepted
- People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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Background: 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. Methods: In this retrospective study, 164 singleton pregnancies with isolated FGR were stratified into non-severe FGR (estimated fetal weight [EFW] between the 3rd and 10th percentiles) and severe FGR (EFW <3rd 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. Results: 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. Conclusion: 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.
Keywords: copy number variation sequencing, exome sequencing, fetal growth restriction, Genetic syndrome, Prenatal Diagnosis
Received: 30 Dec 2025; Accepted: 05 Feb 2026.
Copyright: © 2026 Li, Deng, Meng, Lu, Guan, Wei, Long and Qin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ting Qin
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