Completed Pregnancy, Children & Inherited Conditions Genetics & Molecular Biology

Fetal Exome sequencing Translating Ultrasound anomalies (FETUS)

Funder Wellcome Charity-funded
Recipient organisation Wellcome Sanger Institute Source-published name: Wellcome Trust Sanger Institute
Funding £3.5M
Period Oct 2014 — Sept 2017

In plain English

AI plain-English summary

Around 5% of pregnancies show structural anomalies on ultrasound, but current genetic tests miss most single-gene disorders responsible for these problems. This project will sequence the entire exome—the protein-coding part of the genome—of fetuses with such anomalies, along with their parents, to see whether this approach can give parents a clear genetic diagnosis during pregnancy. The problem is that existing tests, like karyotyping and chromosomal microarrays, either miss small mutations or are not yet standard nationwide. Without a genetic diagnosis, clinicians cannot accurately counsel parents about what the anomaly means for their child’s future, or manage the pregnancy and delivery appropriately. This study directly addresses that gap by testing whether rapid exome sequencing can deliver actionable results within the tight timeframe of an ongoing pregnancy. If successful, the research could transform prenatal care. Instead of leaving many parents in uncertainty, routine fetal exome sequencing could identify specific genetic disorders early enough to guide decisions about treatment, delivery planning, or palliative care. The project also develops ethical guidelines and laboratory infrastructure needed to make this service available across the NHS. While the work is applied and clinical, it will simultaneously discover new disease-causing genes, advancing fundamental understanding of human development.

View original technical description
Fetal structural anomalies identified on ultrasound scan are observed in approximately 5% of pregnancies 1. They require accurate counselling of concerned parents, and commonly have a genetic aetiology. Nationwide, current genetic testing is limited to cytogenetic karyotyping (resolution of 5-10Mb), while chromosomal microarray testing, which increases diagnostic yield, is entering clinical practice in some centres. However, many parents do not receive a genetic diagnosis in pregnancy, and most single gene disorders are not identified prospectively. The introduction of genome-wide sequencing promises to improve markedly the counselling offered to parents and enable improved management of the pregnancy and childbirth. We will prospectively assess the clinical utility and cost-effectiveness of sequencing fetal and parental exomes and genomes, using fetal DNA obtained after invasive sampling for standard investigations of structural anomalies. Sequencing will both increase diagnostic yield and enable discovery of novel genetic disorders. This prospective cohort will be multicentre with two NHS regional genetics laboratories performing DNA preparation and validation, and sequencing at the Wellcome Trust Sanger Institute (WTSI). If a pathogenic genetic disorder is identified, it will be reported, through clinical genetic services, to families after the pregnancy. This study will develop critical enabling resources for rapid prenatal diagnostic sequencing, as well as ethical guidelines, to allow parental counselling and management within the timeframe of the affected pregnancy in the future.

View the original record at the funder ↗

Researchers

Matthew Hurles (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Optimising EXome PREnatal Sequencing Services - EXPRESS
18GR11 - Fetal exome sequencing for prenatal diagnosis in the NHS: identifying challenges, benefits and barriers to ensure appropriate implementation
Fetal exome sequencing for prenatal diagnosis in the NHS: identifying challenges, benefits and barriers to ensure appropriate implementation
Parental views and experiences of prenatal exome sequencing: A sub-study of the Optimising EXome PREnatal Sequencing Services (EXPRESS) project
Parent views and experiences of prenatal exome sequencing: A sub-study of the optimising EXome PRenatal Sequencing Services (EXPRESS) project

Original classification

Health Innovation Challenge Fund Award

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