Congenica, Cambridge, UK, recently led a discussion focused on the bottlenecks of consistency and data-sharing during a presentation at the annual meeting of the American Society of Human Genetics (ASHG).
“There is huge value in being able to share data to see how others have interpreted the same gene variant,” says Matthew Hurles, MD, cofounder of Congenica and a senior group leader at the Wellcome Trust Sanger Institute. “In order to translate research findings into the clinic, genetic results need to be supported with evidence and presented in such a way that clinicians can take forward the findings with confidence.”
Hurles is principal investigator of the Deciphering Developmental Disorders (DDD) study, established between the UK National Health Service and the Wellcome Trust Sanger Institute, and the largest of its kind in the world. Researchers involved in the study have analyzed the exomes of around 14,000 children with severe, undiagnosed developmental disorders, as well as the exomes of their parents. DDD is providing diagnoses for around a third of these families and has identified clusters of affected children that have similar clinical characteristics and shared damaging variants in the same gene.
To support the DDD study, a powerful software platform was developed, leveraging the web portal created as part of the database of genomic variation and phenotype in humans using Ensembl resources (DECIPHER), a data-sharing initiative that is coordinated at the Sanger Institute and used by a global network of clinical centers. The software formed the basis for Congenica’s Sapientia technology, a clinically validated genomics interpretation platform.
Although the main DDD program has been completed, analysis of the data is continuing. “We are getting to a position where we can start to characterize the overall genetic architecture of developmental disorders,” Hurles says. “This is a significant development and will be valuable from a public health perspective. It will enable an estimate to be made of the contribution of the different types of disorders and, through extrapolation, to show how prevalent a disease is in the general population.
“Many of these genetic diseases are so rare that a clinician may see only one or two cases in their career,” Hurles continues. “Being able to compare their patient’s genetics to this growing body of knowledge is a major step forward in helping consultants determine a definitive diagnosis.”
Hurles stresses the importance of data sharing, despite the study’s already large volume of data. “There are some disorders where we only have one child with a particular condition,” Hurles says. “By making sequence variants visible through the DECIPHER web portal, we have enabled clinicians to connect patients with the same mutation, and as a result define new disorders.”
Sapientia provides clinicians and scientists with the tools needed to interpret mutations found using gene panels, exomes, and genomes, and links them to clinical phenotpyes displayed by the patient. It provides a list of filtered, potential disease-causing variants that can be assigned pathogenicity by users.
“Developing a consistent industry-wide approach for retaining this evidence would be a very powerful way to ensure interoperability over time,” Hurles says. “For Sapientia, we are keen to have an open set of standards, which would allow us to capture this information systematically from different sources.”
For more information, visit Congenica.