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Diagnosis Of Fetal Structural Abnormalities Using Exome Sequencing

Diagnosis Of Fetal Structural Abnormalities Using Exome Sequencing

5/14/2020    |    0 min read

As part of the ACMG 2020 Annual Meeting, Louisa Ive, Clinical Scientist, presented work on the use of exome sequencing in the diagnosis of fetal structural anomalies. The study, jointly undertaken by Congenica and St George’s Hospital in London, highlighted the importance of exome sequencing in a prenatal setting to increase diagnostic yield and maximize efficiency.

Due to Covid-19, Louisa’s Platform Presentation was performed virtually. You can watch the video here.

The value of exome sequencing in the prenatal setting

Approximately 3% of pregnancies will have a structural anomaly detected by ultrasound, which can range from an isolated minor finding through to a multisystem, severe phenotype (1). The introduction of prenatal chromosomal microarray testing (CMA) as an investigation for fetuses with sonographic abnormalities has been shown to improve the diagnostic yield by up to 6% compared to conventional karyotyping (2). However, current testing strategies still fail to achieve a diagnosis for the majority of cases. Genetic disorders are known to be the leading cause of morbidity and premature death in the prenatal and neonatal period, and hence understanding the underlying cause in these pregnancies is key for accurate perinatal management and informed decision making.

The Prenatal Assessment of Genomes and Exomes (PAGE) study was the first large UK-based effort to explore the potential benefit of fetal exome sequencing. Next-generation sequencing, specifically exome sequencing, in the prenatal setting has now been consistently shown to have the power to substantially improve the diagnostic yield in fetuses with diverse structural abnormalities first identified by prenatal ultrasound (3). Whilst the yield achieved does vary, some studies have reported a figure as high as 80% (4). Achieving a diagnosis allows for highly personalised management and care during the pregnancy, as well as informing discussions around recurrence risk. 

Maximizing clinical utility 

Congenica have been delivering a rapid exome sequencing service in conjunction with St George’s Hospital in London for over 2 years. To date over 600 cases have been processed and analyzed, with around one fifth of these being prenatal referrals.

The service incorporates a copy number testing element into the pipeline for cases processed using the ExomeCG assay (5), allowing ust geos to provide a single comprehensive test for Single Nucleotide Variants (SNVs), indels and Copy Number Variants (CNVs). Overall, prenatal exome sequencing has yielded a diagnosis in 38% of cases, and a plausible variant of uncertain significance in a number of others. This figure represents cases from a broad range of phenotypic categories, with skeletal dysplasia giving the highest individual yield at 69%. We have also to date identified two cases with CNVs of clinical significance, illustrating the value of this comprehensive service approach.

Our case series includes a number of reports issued with a variant of uncertain significance (VUS) that was subsequently re-classified to pathogenic or likely pathogenic following further exploration of the phenotype and/or familial testing. Previous studies have concluded that where possible parental bloods should be made available to facilitate a trio analysis in order to maximize efficiency and diagnostic yield (6), and our data supports this recommendation. Our findings highlight both the challenge of reduced prenatal phenotypic detail compared to postnatal cohorts, and the importance of expanding prenatal genotype/phenotype understanding.

The power of a single test         

Providing a single comprehensive assay that allows for assessment of SNVs, indels and CNVs in parallel reduces both the cost of testing and time to diagnosis, which is of particular importance in a prenatal setting where a rapid result is often critical. To date we have identified two cases with both a causal SNV and CNV in parallel; one in a fetus presenting with multiple structural anomalies alongside hydrops, and the other with a skeletal dysplasia phenotype. Our CNV data generated using an enhanced exome design (ExomeCG) suggests exome sequencing data is effective for identifying genomic structural findings of clinical significance.

Towards genomics-driven care

Prenatal testing strategy choice and selection should be guided by the family history as well as imaging findings. A genetic diagnosis guides individualized prenatal care, including reproductive decision making, neonatal management and in some cases in utero therapy – there is significant potential to decrease perinatal morbidity and mortality as well as inform genetic counselling around recurrence risk. Our case series supports the use of exome sequencing to increase diagnostic yield whilst maximizing efficiency.


Rapidly identify the cause of prenatal fetal anomalies

Prenatal genetic diagnosis is a critical but complex clinical challenge to inform decisions during pregnancy and after birth. To support the analysis of ultrasound-detected fetal anomalies faster than ever before, we have developed Congenica Prenatal, a pre-configured application available within our clinical decision support platform, with expert curated and annotated gene panels, enabling you to rapidly identify the molecular cause of fetal anomalies.

Find Out More



  1. Persson M, et al. BMJ. 2017 Jun; 357:j2563
  2. Callaway JL, et al. Prenat Diagn. 2013 Dec;33(12):1119-23
  3. Carass KJ, et al. Hum Mol Genet. 2014 Jun 15;23(12):3269-77
  4. Best S, et al. Prenat Diagn. 2018 Jan;38(1):10-19
  5. Nonacus (2019), https://nonacus.com/nonacus-introduces-exomecg-product-to-simplify-molecular-and-cytogenomics-data-generation-and-interpretation/
  6. Drury S, et al. Prenat Diagn. 2015 Oct;35(10):1010-7