Institute of Metabolism and Systems Research, College of Medical & Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
Fetal Medicine Centre, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Ultrasound Obstet Gynecol. 2021 Oct;58(4):509-518. doi: 10.1002/uog.23652.
To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF).
A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected).
In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51).
Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
确定外显子组测序（ES）相对于染色体微阵列分析（CMA）或核型分析在产前诊断非免疫性胎儿水肿（NIHF）中的增量收益。
进行了一项前瞻性队列研究（包括产前基因组和外显子组评估（PAGE）研究的扩展组），其中包括 28 例经阴性 CMA 或核型分析后进行三体外显子组 ES 检测的产前诊断 NIHF 病例。这些病例与文献系统评价中的数据相结合。电子检索 MEDLINE、EMBASE、CINAHL 和 ClinicalTrials.gov 数据库（2000 年 1 月至 2020 年 10 月），以获取关于产前检测到 NIHF 的胎儿中 ES 相对于 CMA 或核型分析的增量收益的研究报告。系统评价的纳入标准为：（i）至少有 2 例 NIHF 进行测序；（ii）根据产前超声表型启动检测；（iii）CMA 或核型结果为阴性。评估 ES 的增量诊断收益的标准为：（i）所有 NIHF 病例；（ii）孤立性 NIHF；（iii）与额外胎儿结构异常相关的 NIHF；以及（iv）根据严重程度的 NIHF（即，受影响的腔隙为 2 个 vs 3 个或更多）。
在扩展的 PAGE 研究队列中，ES 相对于 CMA 或核型分析的额外诊断收益在所有 NIHF 病例中为 25.0%（28 例中的 7 例），在孤立性 NIHF 中为 21.4%（14 例中的 3 例），在非孤立性 NIHF 中为 28.6%（14 例中的 4 例）。在荟萃分析中，基于 21 项研究（306 例）的汇总增量收益为 29%（95%CI，24-34%；P<0.00001；I=0%），在所有 NIHF 中为 21%（95%CI，13-30%；P<0.00001；I=0%），在孤立性 NIHF 中为 39%（95%CI，30-49%；P<0.00001；I=1%），在与额外胎儿结构异常相关的 NIHF 中为 39%。在后一组中，先天性肢体挛缩是最常见的与致病变异相关的额外结构异常，在 110 例有致病变异的病例中发生了 17.3%（19/110）。根据水肿严重程度，增量收益没有显著差异。最常见的确定遗传疾病是 RAS 相关疾病，在 89 例有致病变异的病例中发生率为 30.3%（27/89），最常见的是由于 PTPN11 变异（44.4%；12/27）。致病变异的主要遗传模式为常染色体显性遗传，在单等位基因疾病基因中为 57.3%（89 例中的 51 例），大多数为新生（86.3%；44/51）。
在制定临床路径时，应考虑在孤立性和非孤立性 NIHF 中使用产前下一代测序。鉴于 NIHF 的潜在综合征诊断范围广泛，且产前表型存在异质性，外显子组或全基因组测序可能比靶向基因panel 检测策略更适合作为检测方法。© 2021 作者。约翰威立父子出版公司出版的《超声妇产科杂志》由国际妇产科超声学会代表。
