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Clinical utility of exome sequencing in pregnancy loss

A recent study, published in Genetics in Medicine, has explored the clinical utility of exome sequencing for detecting monogenic aetiology of pregnancy loss.

Pregnancy loss

The loss of pregnancy ranges from spontaneous abortion or miscarriage to stillbirth, which estimates suggest is around 30%. Pregnancy loss can have a significant physiologic and psychological impact on women and their families. Identifying underlying genetic causes, in some cases, could help reduce self-blame and allow for effective clinical management during future pregnancies.

Researchers have found several genetic abnormalities that cause pregnancy loss, typically through diagnostic karyotyping and microarray analysis. Experts have found both numerical and structural chromosomal abnormalities and pathogenic copy-number variations in 50% and 4% of production of conception (POC) cases, respectively. Further investigation of these changes has revealed critical candidate genes and potential interactive gene networks affecting early embryonic development. For example, the first report of exome sequencing on a family with recurrent pregnancy loss identified a homozygous rare variant in a highly conserved region of the CHRNA1 gene. Accumulated research data has indicated that exome sequencing may be instrumental in identifying monogenic causes for a large proportion of pregnancy loss cases. Thereby, emphasising the importance of integrating exome sequencing into diagnostic practice.

Exome sequencing

In this study, researchers performed exome sequencing on a cohort of 102 POC samples with normal chromosome and microarray findings. The team also evaluated the feasibility and sensitivity of this assay. The ACMG/AMP guidelines were used to classify variants. Result interpretation was given by disease association and the possibility of prenatal lethality.

Exome sequencing detected 6 pathogenic variants, 16 likely pathogenic variants and 17 variants of uncertain significance favour pathogenic (VUSfp). The abnormality detection rate for pathogenic and likely pathogenic variants was 22% and reached 35% with inclusion of VUSfp. Additionally, the abnormality detection rate of spontaneous abortion and stillbirth were 36% and 33%, respectively. The genes affected included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders and renal diseases.

This study has demonstrated that 22–35% of pregnancy losses have variants of diagnostic value in genes that may contribute to foetal death. Consequently, this supports the use of exome sequencing as a valuable tool in searching for a cause for pregnancy loss. The identification of disease-associated variants is also important as it can provide information for follow-up genetic counselling and management of subsequent pregnancies.

Image credit: By ktsimage –