We’ve taken the approach of combining whole genome sequencing (WGS) with in-silico panel analysis for three key reasons:
1. Avoidance of amplification bias
First, PCR-free WGS avoids the bias of amplification-based NGS methods used by targeted panel and exome tests. This provides consistent, even coverage across the entire genome which provides even better coverage of the variants typically identified by these types of tests.
2. Detection of additional variant types
As a second benefit, the consistent, even coverage makes it possible to identify other types of variants often missed by these types of tests. Including deletions and duplications of all sizes big and small as well as short tandem repeat expansions.
3. Ability to reanalyze the data at any time
The third key reason is that once you have the entire DNA sequence available, you can perform any relevant analysis at any time. We most often think of this in the traditional context of exome reanalysis. Many publications in recent years have demonstrated the value of reanalyzing exome data 18 months to 2 years after an initial negative result. This isn’t surprising. At the end of the day, analysis of variants identified by any NGS method is heavily dependent on what is known in the scientific literature about those variants. And as collective knowledge grows through ever more studies and ever more publications, previously uncharacterized variants will become better understood. For a deeper dive into this topic, see our earlier post.
What’s not often considered is that the ability to perform any relevant analysis at any time makes it possible to start with a targeted testing approach and quickly reflex up to a broader test. This is the in-silico panel approach.
Why consider this approach?
Why might a physician wish to take a more narrow, in-silico panel approach instead of going directly to a comprehensive analysis of all variants? One reason might be that broad testing isn’t supported by the patient’s insurance. Another might be the desire to leave counseling of patients regarding potential incidental findings to those with deeper training in the broader disease indications covered in the ACMG59 recommended list of genes and conditions. Yet another reason might simply be a preference for a targeted approach that starts narrow and progressively becomes more broad with each reflex following a negative result.
When WGS is the backbone technology, an in-silico panel can technically be as small as a single gene or as large as the exome. We’ve taken an initial approach of creating in-silico panels by therapeutic area. Individual panels ranging in size from ~300 to 1,000+ genes are offered for epilepsy, intellectual disability and movement disorders, which are sub panels of a larger, all inclusive neurology panel. Mitochondrial and endocrine disorders are the focus of two additional panels. All provide the option to reflex up to a more comprehensive genome-wide analysis with a negative result.
Read our follow up post where we look at an additional advantage of the in-silico panel approach: the ability to adapt the components of the panel at any time based on our ever-evolving understanding of human disease.