Purpose

Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss.

Methods

A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated.

Results

ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases.

Conclusion

These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

中文翻译：

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受孕产物的外显子组测序分析：一项评估流产临床效用和遗传病因的队列研究

目的

从自然流产 (SAB) 到死产的流产可能是由孟德尔遗传的单基因原因引起的。本研究评估了外显子组测序 (ES) 在确定流产遗传病因中的临床应用。

方法

为 ES 选择了 102 个来自具有正常核型和不存在致病性拷贝数变异的受孕产物 (POC) 标本的队列。评估了与 SAB 和死产相关的异常检出率 (ADR) 和诊断价值变量。

结果

ES 从该队列中检测到 6 个致病变异、16 个可能的致病变异和 17 个意义不确定的变异有利于致病（VUSfp）。致病性和可能致病性变异的 ADR 为 22%，包含 VUSfp 后达到 35%。SAB 和死产的 ADR 分别为 36% 和 33%。受影响的基因包括与多系统异常、神经发育障碍、心脏异常、骨骼发育不良、代谢紊乱和肾脏疾病相关的基因。

结论

这些结果支持 ES 用于检测流产单基因病因的临床效用。疾病相关变异的鉴定为复发风险的后续遗传咨询和后续妊娠的管理提供了信息。新变异的发现可以为导致胎儿死亡的潜在分子机制提供洞察力。