In the last three years there has been an exponential growth in genetic knowledge, which has seen the identification of nearly 30 new disease genes every month, creating a major challenge for clinical diagnostic services.
At present, testing for over 600 disorders is available within the UK National Health Service, but this represents only a fraction of the known disease genes and these tests are performed sequentially. The introduction of whole genome sequencing has the potential to drastically improve the quality and speed of diagnosis and reduce the cost. The 100,000 Genomes Project is studying rare diseases to provide proof of concept for a unified genomic data platform. Over 80% of rare diseases are caused by the mutation of a single gene, providing a clear association between a single-gene defect and its expression in disease symptoms, or “phenotype”. This makes it easier to validate a systematic approach.
As a result of the falling price of sequencing and improved understanding of ‘omics’ – genomics, transcriptomics, proteomics and metabolomics – we are starting to see the reclassification of disease according to its genetic origin rather than its physical location when detected. This is driving change throughout every branch of medicine, from diagnosis through to drug development.
Limitations of current methods
Rare disease caused by gene mutation
It is estimated that 350 million people worldwide suffer with a rare disease; although the number of people diagnosed with each individual condition is relatively small, there are over 7,000 diseases currently identified. These diseases are most frequently first identified when children fail to reach key developmental milestones. As around 70% of these diseases are life limiting, it is important to reach a diagnosis as quickly as possible, even before symptoms appear. However, diagnosing these diseases can be a very long and frustrating experience, as hospital consultants may see only one or two cases in their whole career and identifying a rare disease by the clinical features is difficult; many different conditions share similar symptoms and these may vary according to the individual.
Rare disease caused by gene mutation
Looking at the genotype of the patient can give an accurate diagnosis at a molecular level. For the family this information is vital. A positive diagnosis may identify effective treatment, and even where treatments are not yet known, it allows them to plan for the future, join relevant patient support groups, and receive appropriate health, education and welfare provisions.
Most genetic testing has been limited to tests for a single gene or small panel of genes that were known to cause disease. If it was found not to be this gene, then further tests were performed to eliminate mutations in different genes sequentially.
As the cost of sequencing has fallen, whole exome and genome sequencing is giving real hope to patients who have not found answers through conventional testing methods. Whole genome analysis has the potential not only to improve the quality and speed of diagnosis but also, as it eliminates unnecessary testing and consultations, to reduce its cost, both for the patient and hospitals.
Current clinical practices
Genetic testing centres vary significantly in the technology they use for DNA sequencing and analysis. Some laboratories have set up their own sequencing and analysis pipelines, whilst others are using commercially available systems.
The genetic tests that are available also differ, depending on the hospital and their specialism. Most tests being offered are for single genes or gene panels – a selection of genes known to be associated with certain diseases. These panels need to be updated regularly to include any newly discovered genes in the target disease for which the panel is designed, which can be a time-consuming process.
Patients can have pages of unclassified variants that need to be manually interrogated by a clinical geneticist. During the analysis many different tools can be used to help determine the disease causing mutation. This takes a lot of man-hours. Another drawback of this process is that the analysis is done in isolation. Although some diseases are very rare, it is possible that other genetics labs may already have analysed patients with a similar condition, and currently it is not possible to share and to access this information. It can take days using the current systems to find the mutation that is causing the patients’ phenotype. In order to become a powerful diagnostic tool, part of the analysis will have to be automated, and the analysis pipeline has to meet rigorous standards.
There is a real need to normalise the genetic practice. As whole exome or genome sequencing is adopted in the future it will enable sharing and direct comparison of data sets so that, as the number of newly identified variants increases, the processing and interpretation of genetic and clinical data become more efficient.
Sapientia automated interpretation and diagnosis support
Sapientia™ is a clinical decision support platform developed by Congenica, a spinout from the Wellcome Trust Sanger Institute founded by six world leading experts in genomics, including Dr Richard Durbin and Dr Matthew Hurles.
Interpretation developed for the Human Genome Project
Sapientia technology is built on the work of Dr Richard Durbin, Senior Group Leader of the Genome Informatics Group and Acting Head of Computational Genomics at the Sanger Institute.
Dr Durbin developed techniques to identify, annotate and interpret whole genome DNA sequence data while working on the Human Genome Project. These methods have accelerated the analysis process, making it easier to see the genes associated with disease.
Validated in the Deciphering Developmental Disorders (DDD) study
These approaches were then further developed within the ground-breaking ‘Deciphering Developmental Disorders’ (DDD) study, a collaborative project between the Sanger Institute, led by Dr Matthew Hurles, and the UK National Health System. It has so far genotyped around 14,000 children with undiagnosed conditions, and their parents, providing diagnoses for around 40% of these families. The results so far have been published in over 15 peer-reviewed journals including a paper in Nature linking 12 novel genes to developmental disorders (Fitzgerald et al, 2015). This work also showed that although every person has around 100-150 mutations, for most of them these changes do not cause disease as they are in non-essential regions of the DNA. This suggests that it is sufficient to use a small section of the genome for detection of the disease-causing mutations.
The DDD study showed that once high quality genetic data have been generated along with excellent phenotypic records, it is possible to analyse and interpret these data and reach a definitive diagnosis for some families in just a few minutes.
Interpretation platform for Genomics England
Sapientia is being used within the 100,000 Genomes Project for clinical interpretation and has been independently validated by Genomics England. The project aims to establish a platform for the application of high-throughput genomics in routine NHS practice. It aims to sequence 100,000 whole genomes from NHS patients by 2017. The project is focused primarily on patients with rare diseases (and their families), and patients with a range of cancers.
Congenica is providing genome interpretation for the 100,000 Genomes Project and is working closely with NHS Genetics Centres to ensure that the tool is optimised to reduce the workload of the labs and to support consultants in diagnosing rare genetic diseases.
Sapientia as a clinical diagnostic platform
Congenica has received both private and public funding in the form of an Innovate UK grant to further develop Sapientia as a clinical diagnostic platform. As exome and genome sequencing is adopted into routine clinical practice, the ability to analyse and interpret large datasets will be critical to ensure timely and accurate diagnosis for patients.
Sapientia enables a significant increase in diagnostic yield, shorter test turnaround times, and improved clinical decision support for identifying disease-causing mutations. This will allow doctors to implement a more personalised management and treatment plan for the patient. It is already being used within the NHS, for example at the Manchester Centre for Genomic Medicine and Great Ormond Street Hospital for Children in London, to help improve genetic diagnosis.
Knowledge base accelerates diagnostic process
One of Sapientia’s key features is its knowledge base. Clinicians annotate each specific mutation associated with a certain illness and/or disabilities by adding phenotypic patient data, scientific publications and detailed notes, and these annotations are stored with the variant. By incorporating this knowledge into the platform, other users can more quickly diagnose patients with the same mutations by highlighting gene-disease relationships.
The more patients diagnosed using Sapientia the more comprehensive the knowledge base will become, improving diagnosis time and accuracy whilst creating a virtuous cycle for future patients. To date, several hospitals in the UK are working with Congenica to upload their archive data to create resource data sets that can be compared to new patient genotypes.
As the primary sequence data is not shared, the data added to the system is not traceable to an individual. If the clinician would like to know further information about other patient’s with similar characteristics in the knowledge base, they would have to contact the physician treating the patient, facilitated by Congenica.
Towards a multi-omics approach
The Sapientia software is continually being developed to include new features in response to the needs of our clients and partners. Congenica was recently awarded an Innovate UK grant to extend its capabilities towards transcriptomics (mRNA) and proteomics (protein). By knowing how the mutation affects the metabolic pathways within the cell, the clinician will be able to implement a more personalised management and treatment plan for a patient diagnosed with a rare disease.
- Fitzgerald TW, Gerety SS, Jones WD, Jones M, van Kogelenbery M et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015 Mar 12;519 (7542): 223-8