In about 3% of pregnancies a fetal anomaly is detected by ultrasound; knowing the cause would greatly assist an accurate diagnosis and provide information about the potential health implications. Currently there are limited genetic tests available, so a project coordinated by the Wellcome Trust Sanger Institute aims to evaluate the use of exome sequencing for this purpose and has selected Congenica’s Sapientia™ technology to support the interpretation of genetic variants.
The PAGE (Prenatal Assessment of Genomes and Exomes) project is funded by a Health Innovation Challenge Fund (HICF) award and is a collaboration between the Wellcome Trust Sanger Institute and fetal medicine centres across the UK, coordinated by the Birmingham Women’s Foundation Trust and the University College Hospital Foundation Trust.
Next-generation DNA sequencing has revolutionised genetic testing, as it allows many genes to be analysed in a single test and the falling cost of the technology has made it more cost-effective for medical diagnosis. Although the whole genome can be sequenced, attention is focused on the exons, regions of the genome that code for proteins. The exome accounts for only 1-2% of the genome but it contain 85% of the mutations known to cause genetic disorders.
PAGE will analyse 1,000 fetal exome sequences, and those of the parents, in a trio design, and will also trial whole genome sequencing in a smaller group. The intention is to create a better understanding of how different forms of genetic variation result in prenatal structural anomalies and to identify those associated with disease.
Dr Nick Lench, Chief Operating Officer at Congenica (pictured above), explains the difficulties of interpreting the relevance of genetic variance in a prenatal setting: “The anomaly is typically picked up by the ultrasound but this provides limited information about the implications for health. For example it is not possible to assess developmental delay and therefore the impact that it will have on quality of life. Knowing the genetic cause aids a more accurate diagnosis and provides information about prognosis and the recurrence risk for parents.”
One aim of PAGE is to design a novel assay that would support prenatal diagnosis. By creating a platform for curating knowledge of gene-disease associations Sapientia will help develop the evidence base that is needed to support NHS adoption of prenatal diagnostic sequencing.
Sapientia will be used in the project to highlight where sections of the DNA are deleted or duplicated, known as copy number variants (CNV), as well as single nucleotide variants (SNV) in the sequences that code for proteins. This information is then displayed graphically and annotated where it is known that the variant has an association with disease. This knowledge is drawn from observations by clinicians and published literature and will be further developed in the project.
Dr Lench continues: “PAGE is a research project and due to current timescales for testing the results will be made available to women and their partners only after the pregnancy is complete. As the minimum amount and quality of DNA needed is explored and experience is gained in interpreting the results, the reporting process will get quicker, offering the potential in future to provide a diagnosis early in pregnancy.”
The PAGE project aims to provide clear information to couples, rather than adding to uncertainty, and so it has opted to provide feedback only on the variants known to be the cause of structural abnormalities seen on the ultrasound scan. Any ambiguities will be assessed by a clinical review panel. In parallel the project will seek to establish an ethical and social science framework for clinical implementation, in order to support patients at a time when they are faced with making complex and difficult decisions.
The PAGE project was funded by a Health Innovation Challenge Fund (HICF) award by the Wellcome Trust alongside the Department of Health (England) and its aim is to answer questions regarding the use of exome sequencing as a diagnostic tool when a prenatal ultrasound examination reveals a structural anomaly. More information: Prenatal exome sequencing for fetuses with structural abnormalities: the next step, Ultrasound in Obstetrics & Gynecology Vol 45, Issue 1 January 2015 pages 4-9