Latest research round-up: April 2023

From our research community: February to April 2023

Here, we showcase some notable recent research that uses data from our National Genomic Research Library (NGRL).

Cherry-picked by our research management team, these studies show how participants – many of whom are from the 100,000 Genomes Project – have played a vital role in research discoveries by volunteering their data to the NGRL.

1) Identifying rare gene variants using the ‘Rareservoir’

Performing genome sequencing on large, diverse groups of people with rare conditions could help us to identify new genetic causes. One of the major challenges of this, is building a system powerful enough to handle large amounts of genomic and medical data.

In this study, researchers use a newly designed database called the ‘Rareservoir’. The Rareservoir contains data from over 77,000 participants of the 100,000 Genomes Project. However, by only holding the rare gene variants from each person’s genome, the Rareservoir makes data storage and processing much more efficient.

Using the Rareservoir, researchers identified 19 previously unreported gene variants that link to specific conditions, 3 of which were confirmed by further investigations. One of the genes relates to primary lymphoedema (chronic swelling), one to Loeys-Dietz syndrome (connective tissue disorder), and the other to congenital hearing impairment.

This research provides real-life examples of how large-scale genome sequencing, paired with efficient data processing tools, can help us discover unknown genetic causes for rare conditions.

2) Identifying new genes for craniosynostosis panel tests

Craniosynostosis is a rare condition where structures in the skull called cranial sutures do not develop properly before birth. It affects around 1 in 2000 children, and results in an unusual shape of the head.

Craniosynostosis is difficult to genetically diagnose, because it varies largely in how it is caused and how it presents in patients.

Gene panels are tests that analyse several genes at once to pinpoint any abnormalities. The Genomics England PanelApp is a set of panels that lets researchers prioritise genes known to cause a specific condition.

For conditions with variable causes, such as craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed.

This recent study repeated a 42-gene panel test on 617 individuals with craniosynostosis. Researchers identified 16 genes that should be added to the current craniosynostosis gene panel, which would increase the current set by 25%.

Incorporating these extra genes into the current PanelApp for craniosynostosis could help provide further genetic diagnoses for participants in the 100,000 Genomes Project.

3) Investigating genetic causes of intellectual disability

A large fraction of patients with intellectual disability (ID) are without a concrete genetic diagnosis.

At most, 40% of cases can be explained by ‘de novo mutations’, which are genetic changes not inherited from parents. The potential role of these changes in causing ID is poorly understood.

This study sequenced a total of 63 genomes, 21 from individuals with ID, the rest from their unaffected parents. Researchers also analysed previously sequenced genomes from ID patients in the 100,000 Genomes Project, all of whom were without a genetic diagnosis.

The study found that de novo mutations were present at more often in DNA sequences that are specifically active during fetal brain development, but not in the adult brain. These sequences were also found to be associated with genes that are expressed in the prefrontal cortex of the brain, which helps to regulate our thoughts, actions and emotions.

Overall, this research provides new evidence that de novo mutations in specific parts of the genome play a vital role in causing ID. These findings could prompt further investigations into the role of these genetic changes in ID and other neurodevelopmental conditions.

4) Looking at mice models for cardiovascular disease

Mice are commonly used as experimental models to investigate human genes and diseases. They have provided us with valuable insights into several conditions, along with potential treatment options. Despite this, transferring findings between mice and humans can be very difficult.

Often, different species possess similar genes that have evolved from one common ancestor. These genes are called orthologues. In this study, researchers use the Genomics England PanelApp to look at mouse orthologues for human genes relating to the function of the heart and blood vessels.

Researchers found that when mice had non-functioning versions of these orthologues, they were far more likely to die than mice with non-functioning orthologues for other human diseases. This suggests that the genes investigated here are essential for organisms to properly develop.

Our understanding of congenital heart conditions in humans is far from complete. However, this study provides valuable insights about the effects of faulty orthologues. This approach could also be used to improve our understanding of other, non-cardiovascular-related conditions.

Research for your reading list

In this section, we highlight some recent research favourites selected by Matt Brown, Chief Scientific Officer here at Genomics England.

Though we may not play a direct part in these research studies, they are certainly relevant to the work that we do.

Studying groups with diverse ancestries reveals gene associations with breast cancer

Kicking it off with diversity; there is a lot we can learn about associations between genes and disease by looking across groups of different ancestries. This includes associations that are essentially hidden unless you look beyond the typical subjects of genomic testing, people of European descent.

A recent study analysed data from individuals of a diverse set of ancestries from the Breast Cancer Association Consortium. 83,471 of these individuals had breast cancer, and 59,199 served as controls.

Researchers identified 14 genes associated with breast cancer amongst European ancestry populations, 2 of which were previously unknown. Then, by combining data from different ancestry groups, they were able to identify further associations, not picked up by analysing European-ancestry groups alone.

This provides further support for the Genomics England Diverse Data initiative. It demonstrates that data from diverse ancestry cohorts will provide value to genetic studies, for rare and common conditions alike.

Mapping the Arab genome

An article in Nature Genetics reports on the Qatar Genome Programme. This programme was established to study the genomics of populations in the Middle East, to enable research across a full spectrum of genetic diseases. Such efforts even include setting up a Qatar biobank.

The Qatar Genome Programme should serve as a reminder of the international impact of Genomics England and the 100,000 Genomes Project. In the article, the authors reflect, ‘We also encourage international research partnerships. For example, we signed a Memorandum of Understanding with Genomics England to share knowledge and experience, and many of our researchers joined the Genomics England Clinical Interpretation Partnership domains.’

Participants of the 100,000 Genomes Project should remember the value or their contributions and the difference that they have made. Their data, combined with the efforts of researchers, has and continues to have a great impact on the world of genomics.

Modelling costs and life-years gained

Moving over to cancer, a vital question for Genomics England is the cost-effectiveness of our methods. A key method used by Genomics England is whole genome sequencing, which allows researchers to look at all of someone’s genetic material in one single test.

A recent study compared the cost-effectiveness of 2 techniques: single gene testing and panel testing. Where single gene testing looks for changes in only one gene, panel testing looks for changes in several genes at once.

The study showed that by shifting all eligible patients from single gene testing to panel testing, the total average cost per life gained would be $16,642 USD. Average cost per life gained is a measure we use to gauge the cost-effectiveness of an approach. In this case, testing the specific FDA-approved panel of genes proved to be very cost-effective indeed!

Currently, the National Institute of Health and Care Excellence recommends interventions costing under £20,000 per quality-of-life year gained. This doesn’t even consider survival improvement. This means, according to this study, that specific panel testing would be a very cost-effective approach for diagnosing cancer.

Data like this would be incredibly useful for whole genome sequencing, helping to support its use in routine cancer care.

Preventing adverse reactions to drugs

Next we have a paper that looks to the future, specifically on the subject of pharmacogenomics.

Pharmacogenomics is the study of how someone’s genetic material may affect their responses to drugs. Currently, adverse drug reactions are involved in 1/15 of NHS hospital appointments, costing the NHS over £2 billion each year.

Whole genome sequencing is a technique that allows researchers to look at all of the genetic material in an individual, using just one single test. By implementing whole genome sequencing into healthcare, it could help to reduce these high rates of adverse drug reactions.

A recent paper reported a study involving 6,944 people screened for 12 genes, all known to influence drug toxicity and drug dosage. Following this screening, genomic data was used to inform drug treatment, and adverse drug reactions decreased by 30% in 2 independent sample populations.

While the study only tested a small subset of gene variants, it shows that genetic screening has great potential to reduce adverse drug reactions. The future looks big for whole genome sequencing in pharmacogenomics.

Discovering genes for cerebral palsy

Finally, we share a paper about the genomics of cerebral palsy. Cerebral palsy refers to a group of conditions that affect coordination and movement. These conditions are life-long, and together form the leading cause of childhood disability world-wide.

Until recently, it was thought that cerebral palsy was exclusively caused by brain damage around the time of birth. For example, restricted oxygen to the baby’s brain caused by trauma during birth. However, recent research has revealed that cerebral palsy might also have a genetic origin.

This paper reviews studies on genome sequencing for cerebral palsy. Across the studies analysed, 2,612 individuals had cerebral palsy, 31% of whom were found to have a causative gene variant. Gene variant discovery occurred at a higher rate in children with intellectual disability or developmental delay than those without. However, the rate of variant identification was significant in both groups.

This study is accompanied by an editorial that calls for genomic screening to be provided for all children with cerebral palsy. This would primarily be to achieve a diagnosis, but also because there are subsets of cerebral palsy where treatments are available. For the time being, judging by the National Test Directory, this isn’t the case for the UK just yet.

Responses to lung cancer immunotherapy

Here we have another paper on cancer, specifically lung cancer, which, despite our advances in immunotherapy, remains the leading global cause of cancer related deaths. A recent study investigated the responses of cells in the immune system, known as B cells, in patients and mouse models with lung adenocarcinoma.

B cells are known for their vital role of producing antibodies to fight infections. They often occur in clusters around tumour tissue, and their presence is linked with improved survival in patients receiving immunotherapy. However, the mechanisms behind this were poorly understood until now.

Investigations revealed that antibodies from B cells were recognising tumours cells as if they were infected by a virus. This is due to ancient viral DNA that has been incorporated into our own DNA throughout evolutionary history. Antibodies attempt to eliminate this, killing cancerous cells in the process.

In national press coverage, authors of the study discuss the potential for cancer vaccines that enhance this effect; not just for therapeutic vaccines, but preventative ones too. A very promising study for progress in cancer therapy.

And there you have it, the latest research round-up. Have something you'd like to add? Leave it in a comment below!

In the meantime, feel free to browse some other technical publications from our research community or take a look at the latest news at Genomics England.