New genomic method enables multiple people with rare conditions to receive diagnoses

A new genomic method has enabled multiple people with rare conditions to receive diagnoses that were previously unattainable by identifying complex structural genetic changes that are often missed by standard tests.

Researchers at the Wellcome Sanger Institute, Genomics England, Cambridge University Hospitals, and their collaborators analyzed the DNA from 13,700 parents and children from the 100,000 Genomes Project. They found that many of these genetic changes, known as structural variants, directly disrupt genes involved in childhood development. 

Published today (3 November) in Nature Communications, this study found that one in eight of these structural variants were complex, often involving multiple changes, and were twice as likely to be missed by current clinical tests.

The researchers have developed a new pipeline that allows them to find these structural variants and were able to classify them into multiple subtypes depending on the impact that the change had on a patient. While some patients had an initial diagnosis, this information provided more in-depth insights that would not have been possible previously. 

The team hope that this method has the potential to help improve the diagnosis and management of rare conditions in the future.

Currently, diagnostic tests for rare conditions mainly focus on identifying single genetic changes – alterations affecting just one of the DNA building blocks at a specific position.

Structural variants are genomic changes that occur when a certain amount of a gene, over 50 building blocks, is rearranged or deleted. When they occur in egg or sperm cells, they can lead to health conditions if they happen in genes that are involved in development.

These variants occur spontaneously, and when this rearrangement happens at multiple places on the genome, this is known as a complex structural variant. All structural variants are difficult and complex to analyse as current genomic testing methods look at short sections of DNA at a time, and seeing structural changes requires testing a larger section of the genome. Piecing these short sections together can be difficult and requires a large amount of technical knowledge, as it is not always clear where they go, and mistakes can lead to false information about the genes impacted.

In this new study, the team at the Sanger Institute and their collaborators built a robust pipeline to overcome these difficulties and identified 1,870 structural variants in 13,700 genomes from families. They found that structural rearrangements play a key role in the development of multiple health conditions, including neurological, skeletal, skin, and neurodevelopmental conditions, as well as those that impact the functioning of the kidneys.

The team was able to provide an updated diagnosis for 145 children with rare conditions by identifying the structural variants, providing answers for their families. Around 60 of these patients have variants that are difficult to detect with other types of genetic tests.

The researchers also noticed that the type of structural rearrangement had an impact on the development of health conditions. Through their analysis, they were able to categorise nine different types of structural variants and show their functional impact in patients.

Further investigation of these categories could help experts understand more about the development of different conditions. In the future, this knowledge may help in the management of health conditions. For example, by understanding how a variant causes a condition to progress, it could be possible to more closely monitor patients for early intervention or develop new ways to tackle or prevent symptoms.

Dr. Hyunchul Jung, first author at the Wellcome Sanger Institute, said: "This new method, which allows us to identify and analyse complex structural variants, opens up new possibilities for the understanding and possibly management of health conditions. We've shown that it's not just about finding a deletion or duplication in the genome, it's how such changes happen together- something that was not possible to see before. Our robust pipeline allows us to look close enough at the genome to start to build a clearer picture for researchers, clinicians, and patients."

These findings show the value that whole genome sequencing can offer and the unique insights it can have – providing families with much-needed answers they have often spent years searching for. Research like this is only possible because of the generous contributions of participants in the 100,000 Genomes Project who have shared their clinical and genomic data to aid impactful work exactly like this. It is fantastic news for the many participants in the pioneering 100,000 Genomes Project, who will receive fresh, long-awaited answers, as well as for families currently seeking diagnoses through genomic medical services."

Professor Matt Brown, Chief Scientific Officer of Genomics England

Professor Helen Firth, co-author at Cambridge University Hospitals, said: "Having a diagnosis often allows families to access support that they couldn't access previously, and in some cases can start to answer questions about why a condition has occurred and help manage it. Structural variants, particularly complex ones, are key in a diagnostic setting, because they can explain otherwise unsolved cases and possibly give clues about how a condition could progress. Our study reveals the scale and clinical importance of complex variants that, until now, were flying under the radar."

Dr. Raheleh Rahbari, senior author at the Wellcome Sanger Institute, said: "Genomic data are an incredibly useful source of information to help diagnose and manage health conditions, and our research shows that expertise is needed to continue to translate insights into something that can help patients. Our new method helps bridge the gap between raw data and diagnosis, and in the future, we hope that this knowledge will also help in the management of health conditions. Incorporating the power of genomic research into clinical pipelines, especially when sequencing is becoming more commonplace in the NHS and globally, can highlight new ways to help patients and families."