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 whole exome sequencing (WES) 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 WES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. Results: WES detected six 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 multi-system abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders and renal diseases. Conclusion: These results supported the clinical utility of WES 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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妊娠产物的全外显子测序分析：一项队列研究，用于评估流产的临床效用和遗传病因

目的：从自然流产（SAB）到死胎的妊娠损失可能是由孟德尔遗传的单基因原因引起的。这项研究评估了全外显子组测序（WES）在鉴定妊娠流产的遗传病因上的临床应用。方法：从102个具有正常核型且无致病性拷贝数变异的受孕产物（POC）样本中选出一组。评估异常检测率（ADR）以及与SAB和死胎相关的诊断值变异。结果：WES检测到该人群的6个病原体，16个可能的病原体和17个不确定性显着的病原体（VUSfp）。包含VUSfp，致病和可能致病变体的ADR为22％，达到35％。SAB和死胎的ADR分别为36％和33％。受影响的基因包括与多系统异常，神经发育疾病，心脏异常，骨骼发育异常，代谢异常和肾脏疾病相关的基因。结论：这些结果支持WES在检测妊娠丢失的单基因病因方面的临床应用。疾病相关变体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。发现新的变体可以为引起胎儿死亡的潜在分子机制提供见解。这些结果支持了WES在检测妊娠丢失的单基因病因方面的临床实用性。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。发现新的变体可以为引起胎儿死亡的潜在分子机制提供见解。这些结果支持了WES在检测妊娠丢失的单基因病因方面的临床实用性。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。新变体的发现可以为引起胎儿死亡的潜在分子机制提供见解。