Detecting Rare Diseases With Whole Exome Sequencing

A rare disease will affect 6% of the population at some point in their lives. Around 80% of rare diseases have a genetic origin and can be attributed to abnormalities or biological triggers in a person’s genome. Symptoms vary widely and can often mirror other more common conditions, resulting in many patients being misdiagnosed. Improvements to diagnostic technologies are needed to help clinicians accurately identify rare diseases and provide appropriate support and treatments where available.

Genomic approaches, such as whole exome sequencing, can provide key information to help experts detect rare diseases, but their use still presents challenges. We recently spoke with Gioia Althoff, Vice President, Genomics, at SOPHiA GENETICS, to learn more about the role that whole exome sequencing can play in the fight against rare diseases and how their new solution can help.

Anna MacDonald (AM): What makes diagnosing and characterizing rare diseases so difficult?

Gioia Althoff (GA): Rare diseases are called rare because there’s not much established data out there for each individual disease that researchers can compare and contrast. This means that the traditional method of diagnosing patients by evaluating a characteristic pattern of signs or symptoms is not sufficient. It requires a lot of effort and resources to understand the real cause of rare diseases, preventing from reaching a quick diagnosis.

Genomics is a new industry that has grown over the past 15 years, having started as a discipline available to only very specialized labs. From its genesis, the renowned Genome Project ultimately took 13 years and cost $2.7 billion. Since then, the costs of such analysis have rapidly decreased. This creates an exponential growth in very complex data generated, which must be properly analyzed, secured and stored.

At SOPHiA GENETICS we are helping lead the global adoption of genomics worldwide to improve healthcare professional's ability to make sense of this data. With an emphasis on precision and data accuracy, the SOPHiA platform supports healthcare institutions with technology for genomics, radiomics and clinical trials to unlock the power of new-generation health data through a powerful AI-based platform and global research community.

AM: What role can whole exome sequencing play? Why is it so challenging?

GA: Rare diseases affect roughly 400 million people globally, and their cause is genomic in approximately 80% of cases. Whole exome analysis has become key as it is extremely powerful in helping experts detect rare diseases, but it remains indeed very challenging. A large amount of information is gathered, making it difficult to properly detect disease-causing DNA variations.

When researchers are confronted with clear symptoms that are commonly linked to a certain health issue, take breast cancer for example, they only need to analyze the relevant genes: here only two, BRCA1/2. In the case of a rare disease, a larger set of genes needs to be taken into account – over 19,000!

Molly Campbell (MC): Why is whole exome sequencing preferable over whole genome sequencing as a diagnostic tool?

GA: Whole exome sequencing is preferred because 85% of disease-causing mutations reside in the exome; also, whole genome sequencing is not ripe at all for now, meaning it’s not accurate enough to be applied at the clinical level.

AM: Can you tell us about SOPHiA GENETICS’ new exome solution?

GA: The solution now includes accurate Copy Number (DNA) Variations detection. That’s a major improvement, given the fact that on average, CNVs are present in almost 10% of patients affected with hereditary diseases and can account for up to 35% of pathogenic variants. The detection of CNVs is very challenging on large panel analysis.

With more accurate CNV detection, the solution reduces the turnaround time to identify rare disease characterization.

The new version of SOPHiA WES also includes Familial Variant Analysis, or trio analysis, to automatically filter data for variants based on different inheritance modes. This capability allows high resolution analysis at the exonic level, at which DNA or RNA molecules contain their coding for protein and peptide sequences. In doing so, SOPHiA WES can offer accurate detection for multiple types of genomic variants at once. Leveraging the analytical power of SOPHiA to further support researchers, WES offers healthcare institutions a standardized genomic solution with exceptional analytical performance. It includes high resolution (2-5 exons) CNV detection in a single workflow without the need for any reference sample.

The updated SOPHiA Whole Exome Solution helps professionals globally manage the daunting amount of detected variants and focus solely on the most relevant ones. With this release, SOPHiA confirms its commitment to overcome barriers in adopting complex genomic applications worldwide by offering robust and standardized solutions.

AM: What are the advantages of a standardized genomic solution for healthcare institutions?

GA: SOPHiA’s solutions allow any hospitals to quickly adopt genomic applications in their routine testing. It saves a lot of time and resources, which is obviously a plus for not only healthcare institutions, but all parties involved. With an emphasis on precision and data accuracy, the SOPHiA platform supports healthcare institutions with technology for genomics, radiomics and clinical trials to unlock the power of data-driven medicine through a powerful AI-based platform and global research community.

AM: What hurdles need to be overcome to further improve the diagnostic process for rare diseases?

GA: Thanks to our Whole Exome solution and the power of SOPHiA, we now have a technology of choice to better and faster characterize and treat rare diseases. Thanks to the global community of over 1,000 healthcare institutions in 82 countries we’ve built, we made the sharing of knowledge possible like never before in healthcare. We now still need to encourage the adoption of such technologies by the largest number of healthcare institutions, so that the data used to help a patient today will benefit those of tomorrow.

Gioia Althoff was speaking to Anna MacDonald and Molly Campbell, Science Writers for Technology Networks.