Supplementary file 1_Severity-stratified genetic diagnosis by trio exome sequencing in isolated fetal growth restriction.xlsx

BackgroundExome 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.
MethodsIn 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 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.
ConclusionThis 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.

【背景】外显子组测序（Exome Sequencing, ES）在产前诊断中的应用日益普及。然而，其在孤立性胎儿生长受限（Fetal Growth Restriction, FGR）中的应用效能，尤其是针对不同严重程度分层的病例，尚未得到充分证实。本研究旨在评估并比较三联体外显子组测序（trio-ES）在孤立性非重度与重度FGR病例中的诊断检出率及临床影响。【方法】本回顾性研究共纳入164例孤立性FGR单胎妊娠病例，按严重程度分层为非重度FGR组（估计胎儿体重[EFW]处于第3至第10百分位之间）与重度FGR组（估计胎儿体重[EFW]低于第3百分位）。【结果】通过trio-ES，非重度FGR组中8.3%（3/36）的病例检出致病或可能致病（Pathogenic or Likely Pathogenic, P/LP）变异，重度FGR组中该比例为18.0%（16/89）。非重度组中所有检出的P/LP变异均与高危表型相关，并导致妊娠终止。重度组中，此类变异与中重度疾病相关，妊娠结局多样（50%的病例终止妊娠）。此外，与非重度组相比，重度FGR组的子痫前期患病率及脐动脉多普勒波形异常率更高，不良妊娠结局可归因于单基因疾病及母胎胎盘因素。【结论】本分层分析显示，ES在孤立性FGR的全严重程度谱系中均具有显著的诊断价值，可在重度与非重度病例中检出具有临床意义的单基因疾病。上述研究结果支持将ES纳入孤立性FGR的诊断流程，无需严格遵循严重程度截断值。同时，本研究强调需开展整合式遗传咨询，以处理意义未明变异及多因素风险，尤其针对重度FGR病例。