145 participants identified with complex genetic changes linked to a rare condition
A new genomic method has identified 145 participants from the 100,000 Genomes Project with a complex genetic change linked to a rare condition, providing some with an explanation for their rare condition for the first time and others with a more precise diagnosis. The complex structural genetic changes identified are often not detected by standard tests, highlighting the benefit that whole genome sequencing can have.
By analysing the DNA from 13,700 parents and children from the 100,000 Genomes Project, Genomics England’s first major research initiative, researchers at the Wellcome Sanger Institute, Genomics England, Cambridge University Hospitals, and their collaborators found that many of these genetic changes, known as structural variants, directly disrupt genes involved in childhood development.
Published today in Nature Communications, this study found that one in eight of these structural variants were complex, often involving multiple changes, and these were twice as likely to be missed by current clinical tests.
The researchers have developed a new pipeline, or step-by-step method, that allows them to spot these genetic changes and classify them into different groups depending on the impact they had on a participant’s genome. They hope that this method has the potential to help improve the diagnosis and management of rare conditions in the future.
Structural variants are changes in large chunks of DNA where segments of DNA can be added, removed, moved to a new location in the genome, or inverted – meaning it is still in the right place but facing in the wrong direction. Structural variants can lead to health conditions if they impact genes associated with a rare disorder.
Structural variants are often difficult and complex to analyse as current genomic testing methods look at short sections of DNA at a time. 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. This makes it difficult to identify some structural variants, especially when multiple regions of the genome are impacted.
In this new study, the research team built a 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 identify 145 participants with a structural variant linked to their rare condition, providing some with an explanation for their rare condition for the first time and others with a more precise diagnosis. They also found 66 of these participants – nearly half – have variants that are difficult to detect with other types of genetic test.
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.
"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 many of the 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
“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.”
Professor Helen Firth
co-author at Cambridge University Hospitals
“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.”
Dr Raheleh Rahbari
senior author at the Wellcome Sanger Institute
