Prenatal Exome sequencing (PES) can be of crucial help to understand abnormalities of fetal structure, posture and behavior where environmental aetiology has been deemed unlikely. Finding the underlying genetic cause faster is highly valuable for prenatal management.
Prenatal testing in the UK
Several techniques are currently used for prenatal testing in the UK, including standard karyotyping (now rarely used in routine practice), quantitative fluorescence polymerase chain reaction (QF-PCR), which is still important, and array-based comparative genomic hybridization (array CHG), which is used to diagnose cases of fetal malformation. Despite these methods, however, there are still many idiopathic cases left – presentations with an unknown cause or mechanism of apparent spontaneous origin.
While exome sequencing can be the diagnostic solution for these cases, it is not yet readily available throughout the UK. However, this is going to change soon via the centralized re-organization of genetic services taking place across the UK National Health Service (NHS) as a continuation of the Genomics England 100,000 Genomes Project.
Current state of prenatal exome sequencing internationally
Throughout the world, prenatal exome sequencing (PES) is still relatively limited and not widely available. In research settings, there are already multiple reports that show an increase in diagnostic yield, and a number of publications show added value of PES in small cohorts.
However, this research has not yet translated to routine clinical practice in the majority of countries and healthcare systems. There has been some application in China, as well as the Netherlands, which has begun to use PES in routine care in a limited way, but largely PES is still restricted to research use.
Preliminary evidence of increased diagnostic yield using exome sequencing
In the cohort described by Dr Dempsey, exome sequencing on prenatal phenotypes was carried out on both ongoing pregnancies (including for some cases rapid analysis of affected live siblings to inform diagnosis of ongoing pregnancies) and post-mortem cases. Much has been published on the diagnostic yield in a variety of cohorts, however, this not necessarily the best measure of the utility of a PES service.
Diagnostic yield can vary widely, with individual publications reporting values between 8.5 % and 75 % [1–4]. This is in large part due to case selection– with specific, homogenous phenotypes demonstrating the greater the diagnostic yield. A lower diagnostic yield can also be a positive, as the impact of a confirmed diagnosis is greater in pregnancies with a more ambiguous phenotype.
Is exome sequencing improving the care we can offer our patients?
Looking at the impact of cases receiving molecular diagnosis, it is evident that exome sequencing has significant management implications. Some examples include:
- Hypophosphatasia – Enzyme replacement therapy commenced at birth
- Anderson-Tawil Syndrome – Mother and child referred to cardiology for treatment to prevent sudden cardiac death
- Noonan syndrome (LZTR1 and RAF1) – pre and postnatal echo. Should hypertrophic cardiomyopathy develop to consider use of MEK inhibitors.
- Hypochondroplasia – Referred for clinical trial
- NR2F2 associated congenital cardiac defects – palliative care at birth
- Mucopolysaccharidosis type II – limited monitoring in labour, neonatal comfort care
Negative results can also influence pregnancy management, for example, parents may choose to continue a pregnancy where there is a credible alternative explanation for fetal malformation.
Analysis of prenatal exome sequencing patients at St George's University Hospitals NHS Foundation Trust, showed that a positive diagnosis had significant management implications in 44% of cases. What’s more, the study showed significant management implications for 8% of cases that received a negative diagnosis.
Prenatal exome sequencing enables informed decision making
Prenatal exome sequencing enables informed decision making; parents can reach out for specialist and peer support and prepare for birth. Importantly, PES shortens or ends the diagnostic odyssey that spares neonates of invasive and costly investigations. Parents can also determine recurrence risks, obtain a molecular diagnosis for preimplantation genetic diagnosis (PGD) or future prenatal tests.
Yet, many cases still remain unexplained: over 50 % remain without a diagnosis during pregnancy. The aetiology can be environmental or genetic but not identified by the sequencing and analysis pipeline, e.g. causes can be intronic, methylation defects, or novel genes.
What does the future hold?
Exome sequencing is increasingly being used in a prenatal setting, and equity of access must be ensured. PES will rely on international collaboration in the centralized collection of genotype-phenotype data, prenatal and post-mortem. Ideally, testing should be done as early as possible. As the technology develops further, time to diagnosis and complex variant interpretation will become easier.
Finding the underlying genetic cause faster with Congenica Prenatal
To help address some of the challenges mentioned, Congenica have developed Congenica Prenatal. This application of the Congenica platform efficiently streamlines interpretation and reporting of prenatal genomic data whilst providing evidence. The first iteration focuses on rapid identification of de novo variants from trios in genes associated with autosomal dominant and x-linked fetal anomalies.
Congenica Prenatal supports the user by signposting to relevant scientific and clinical content, including curated PubMed annotations on genes for prenatal phenotype relevant literature and curated variant lists flag previously well described pathogenic variants such as the ClinGen RASopathy Expert Panel and those identified as disease causing in large cohorts of fetal anomalies .
This, combined with integration of results and evidence into templated reports, reduces time to molecular analysis. In addition, the full Congenica platform can be accessed for a deeper dive of the data should the case be negative for de novo mutations. Congenica Prenatal enables genomic analysis up to 20-times faster and saves an additional 40-minutes per report.
Are you analyzing prenatal cases as efficiently as possible?
Download our Congenica Prenatal data sheet.
 Lord J, McMullan DJ, Eberhardt RY, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 2019;393:747–57. doi:10.1016/S0140-6736(18)31940-8
 Vora NL, Gilmore K, Brandt A, et al. An approach to integrating exome sequencing for fetal structural anomalies into clinical practice. Genet Med. 2020;22(5):954‐961. doi:10.1038/s41436-020-0750-4
 Greenbaum L, Pode-Shakked B, Eisenberg-Barzilai S, et al. Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families. Front Genet. 2019;10:425. Published 2019 Jun 25. doi:10.3389/fgene.2019.00425
 Tang J, Zhou C, Shi H, et al. Prenatal diagnosis of skeletal dysplasias using whole exome sequencing in China. Clin Chim Acta. 2020;507:187‐193. doi:10.1016/j.cca.2020.04.031
 Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 2019;393:758–67. doi:10.1016/S0140-6736(18)32042-7