Abstract：
OBJECTIVE: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification.
METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747.
RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%).
CONCLUSIONS: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.
METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747.
RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%).
CONCLUSIONS: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.
摘要：
目的：为了确定产前外显子组测序（PES）相对于标准测试的增量，在有先天性心脏异常（CHA）的胎儿中，CHA与心脏外畸形（ECM）和CHA相关，取决于解剖亚分类。
方法：使用MEDLINE对文献进行了系统回顾，EMBASE,WebofScience和灰色文献2010年1月至2023年2月。如果标准测试（QF-PCR/染色体微阵列/核型）阴性，则选择研究包括超过20例产前诊断的CHA。确定了汇集的增量产量。PROSPEROCRD42022364747。
结果：总体而言，21项研究,纳入了1957年的案例。PES（致病性和可能的致病性变异）的增量产量超过标准测试为17.4%（95%CI，13.5%-21.6%），所有CHA的9.3%（95%CI，6.6%-12.3%）和35.9%（95%CI，21.0%-52.3%），分离的CHAs和CHAs与ECMs相关。产量最大的亚组是复杂病变/异位；35.2%(95%CI9.7%-65.3%)。最常见的综合征是Kabuki综合征（31/256，12.1%），大多数致病变异是从头和常染色体显性（单等位基因）致病基因（114/224，50.9%）。
结论：多系统CHAs胎儿单基因病因的可能性很高。临床医生必须考虑在选定的孤立心脏病变中提供PES的临床实用性。
方法：使用MEDLINE对文献进行了系统回顾，EMBASE,WebofScience和灰色文献2010年1月至2023年2月。如果标准测试（QF-PCR/染色体微阵列/核型）阴性，则选择研究包括超过20例产前诊断的CHA。确定了汇集的增量产量。PROSPEROCRD42022364747。
结果：总体而言，21项研究,纳入了1957年的案例。PES（致病性和可能的致病性变异）的增量产量超过标准测试为17.4%（95%CI，13.5%-21.6%），所有CHA的9.3%（95%CI，6.6%-12.3%）和35.9%（95%CI，21.0%-52.3%），分离的CHAs和CHAs与ECMs相关。产量最大的亚组是复杂病变/异位；35.2%(95%CI9.7%-65.3%)。最常见的综合征是Kabuki综合征（31/256，12.1%），大多数致病变异是从头和常染色体显性（单等位基因）致病基因（114/224，50.9%）。
结论：多系统CHAs胎儿单基因病因的可能性很高。临床医生必须考虑在选定的孤立心脏病变中提供PES的临床实用性。
