Fetal anomalies affect approximately 3% of pregnancies in the UK but current testing methods are able to detect underlying chromosomal or Mendelian factors in just under half of these cases.
A new, ten-year cohort collaborative study was recently published in Prenatal Diagnosis Journal by Mone et al., with the aim of evaluating the proportion of fetuses where a diagnosis was aided by assessment in the prenatal genetic clinic, and examining trends in fetal genetic testing and the use of new molecular genetic technologies.
The study involved 256 women/couples who attended a combined fetal medicine and clinical genetic clinic at the Birmingham Women’s and Children’s NHS Foundation Trust between May 2008 and April 2019. The MDT in this clinic included fetal medicine consultants, clinical geneticists, genetic scientists, genetic midwife, prenatal genetic clinical fellows and genetic counsellors. The inclusion criteria included a chromosomal or genetic abnormality in a previous pregnancy, personal or family history of a genetic disorder, recurring congenital anomalies and fetal structural anomalies suggestive of a genetic disorder. Of particular note was the high prevalence of parental consanguinity in the cohort.
Below we outline some of the key findings from the study.
Current and Future Methods for Prenatal Diagnosis in the Clinic
Identification of the fetal phenotype can be challenging; clinical fetal examination is currently restricted to ultrasound and in-utero magnetic resonance imaging, which give a limited picture of phenotypes.
Previously, G- banding was used to identify chromosomal abnormalities. This was subsequently replaced by comparative genome hybridisation microarray assessment (CMA) and quantitative fluorescent polymerase chain reaction (QF-PCR). Genetic analysis by way of exome sequencing and genome sequencing (ES and GS) can also be performed on postnatal or post-mortem samples, as was the case in this study. This can aid in the management or treatment of the current pregnancy as well as subsequent pregnancies. Moving forward, ES and GS will become increasingly more common in fetal diagnostic services and require the involvement of an MDT review panel. A fast turnaround is also required, due to the limited time scales in prenatal diagnosis.
Genetic counselling, accurate phenotyping and interpretation of genetic findings are a crucial part of prenatal diagnosis. Clinical geneticists and fetal medicine subspecialists play a key role in this, but the diagnostic process can be further optimized by implementing multi-disciplinary teams (MDT) that include genetic laboratory staff, perinatal pathologists, genetic nurse counsellors and midwives.
Key Results from the Mone et al. Study
In this study, in the instance of a fetal structural anomaly or increased nuchal translucency, prenatal invasive testing was performed in the form of amniocentesis, chorionic villous sampling or fetal blood samples. In the early years of the study (2008 – 2011), quantitative fluorescent polymerase chain reaction (QF-PCR) was performed; followed by introduction of comparative hybridisation microarray assessment (CMA) between 2011 - 2014.
Additionally, fetal ES was employed from 2014 as part of the Prenatal Assessment of Exomes and Genomes (PAGE) study, in which ES was performed using TruSight One Expand (Illumina) with trio analysis using the Congenica platform. The panels used comprised of 1542 genes which were relevant to prenatal conditions. This was based upon the Deciphering Developmental Disorders (DDD) study.
In total, a definitive clinical or genetic diagnosis was achieved in 47.7% of the cases. Non-genetic diagnoses were reached through neonatal or post-mortem examination, whereas genetic diagnoses were made through chromosomal or single gene testing, following fetal structural anomaly detection on ultrasound, 50.6% of which was achieved prenatally. The median time taken to achieve such a diagnosis was 28 days. The high ratio of cases diagnosed in the postnatal period illustrates the value of postnatal external examination and post-mortem investigation and this has been described in detail by the authors elsewhere (Quinlan-Jones et al 2019).
Changing Trends in Prenatal Diagnosis
When comparing diagnostic rate between different eras of testing - QF-PCR (2008-2011), CMA (2011-2014) and ES (2014-2019) - there was no significant difference found (31.7%, 29.1% and 31.3%, respectively).
Investigation of the diagnostic methods applied during these eras clearly showed a shift towards using ES as the predominant testing method in the prenatal setting, which has led to a reduction in the time to diagnosis. ES data may help improve our understanding of rare diseases or well-established disorders without a known prenatal phenotype. Going forward, ES will become a key testing methodology in the prenatal setting due to increased diagnostic yield. This will improve our ability to council the parents regarding prognosis, treatment and future reproductive decisions.
Translating Research-Based Technologies into Clinical Practice
The changes in trends seen in this study demonstrate the value of translating research-based technologies into clinical practice. This was particularly evident in the implementation of ES in prenatal diagnostics. The increasing use of such technology reflects the desire to understand the cause of the fetal condition, as well as the impact this information can have on both pre- and postnatal management options and potential occurrence in future pregnancies.
Analysis platforms that can facilitate efficient and accurate ES interpretation in the prenatal setting will also become of increasing importance. As the volume of prenatal ES data increases, analysis of data will need to be performed with increasing efficiency to ensure timely and accurate return of results.
Rapidly identify the cause of prenatal fetal anomalies
Platforms such as Congenica Prenatal can support the research of implementing prenatal genomic testing into clinical practice by increasing the efficiency of analysis, reducing the amount of manual interpretation required, and supporting MDTs that include key specialists.
Find out how Congenica Prenatal can help you streamline analysis and interpretation of prenatal genomic data and provide information faster than ever before by booking a personalised demo with a member of our team: