Table 2_Exome sequencing and prenatal skeletal abnormalities: comprehensive review and meta-analysis and way forward.doc

ObjectiveTo assess the detection rate of exome sequencing (ES) in fetuses diagnosed as skeletal abnormalities (SKA) with normal karyotype or chromosomal microarray analysis (CMA) results. MethodsWe conducted electronic searches in four databases, focusing on studies involving ES in fetuses with SKA. Additional detection rate of ES compared to karyotype/CMA was calculated, followed by a meta-analysis. Subgroup analyses explored the influence of fetal phenotype on diagnostic outcomes. ResultsFrom 2,393 studies, 21 reports covering 476 fetuses were analyzed. Key findings include: (1) an additional detection rate of ES of 63.2% (Risk Difference (RD), 0.68 [95% CI, 0.60–0.76], p < 0.00001); (2) identification of 76 genes across 304 types of variants, with FGFR3, COL1A1, COL1A2, and COL2A1 being prevalent; (3) lower detection rates in fetuses with isolated short long bones compared to non-isolated conditions, though not significantly different (p = 0.35); (4) higher detection rates in subgroups with abnormal ossification, small chest, suspected long bone fractures or angulations, and skull abnormalities. ConclusionThe meta-analysis indicates that genetic variation significantly contributes to fetal SKA, primarily due to single-gene variants. Consequently, ES should be used in the prenatal diagnosis of SKA fetuses in clinical practice.研究目的：评估针对核型分析或染色体微阵列分析（chromosomal microarray analysis, CMA）结果正常、被诊断为骨骼异常（skeletal abnormalities, SKA）的胎儿，外显子组测序（exome sequencing, ES）的检出率。 研究方法：本研究在4个数据库中开展电子检索，聚焦于针对骨骼异常胎儿实施外显子组测序的相关研究。计算外显子组测序相较于核型分析/CMA的额外检出率，并进行荟萃分析。亚组分析旨在探究胎儿表型对诊断结局的影响。 研究结果：从2393项初始研究中，最终纳入21篇报道、共476例胎儿进行分析。核心发现包括：（1）外显子组测序的额外检出率为63.2%（风险差（Risk Difference, RD）为0.68[95%置信区间（CI）：0.60~0.76]，p < 0.00001）；（2）共鉴定出304种变异类型，涉及76个基因，其中FGFR3、COL1A1、COL1A2及COL2A1为高频致病基因；（3）孤立性长骨短缩胎儿的检出率低于非孤立性病例，但差异无统计学意义（p = 0.35）；（4）在骨化异常、小胸廓、疑似长骨骨折或成角畸形、颅骨异常的亚组中，检出率显著更高。 研究结论：本次荟萃分析结果表明，遗传变异是胎儿骨骼异常的重要致病基础，其中以单基因变异为主。因此，临床实践中应将外显子组测序应用于骨骼异常胎儿的产前诊断工作中。