Leading with quality: Deletions and duplications

Did you know that Invitae analyzes deletions and duplications for each and every gene in all our panel tests at no additional charge? Diagnostic genetic testing requires a carefully constructed medical assay to thoroughly interrogate genes of interest. Invitae’s assays comprehensively report sequence changes and deletion/duplication events in coding exons, splice sites, and other regions known to harbor pathogenic mutations.

What are deletions and duplications?
Copy-number variants (CNVs) include gross deletions (losses) or duplications (gains) of DNA material. Relatively small CNVs, ranging in size from a single exon to a full gene, are often called del/dup events in order to distinguish them from larger CNVs detected by traditional cytogenetic methods. Invitae’s assay focuses on accurately detecting these del/dup events. In addition, while not intended to replace cytogenetics, Invitae’s assay also detects larger CNVs involving multiple genes when those genes are part of a test order. Del/dups can account for a significant proportion of pathogenic changes in hereditary disorders.

Why are deletions and duplications clinically important?
Accurate del/dup analysis is essential to genetic diagnosis. DNA sequence analysis alone will usually miss del/dup events—yet these types of genetic changes can affect gene function and explain disease. Del/dup events are found in 9.8% of patients with a positive Invitae test (Truty 2018, in press). In some clinical areas, the frequency is much greater; in neurology, it is 35%. Other commercially available gene panels and standard exome sequencing do not always include del/dup testing which can result in missing an important genetic change.

What is Invitae’s approach to deletions and duplications?
Invitae uses next-generation sequencing (NGS) to conduct intragenic del/dup analysis alongside the detection of sequence variants. To detect del/dups, our NGS approach uses a customized, validated set of computer algorithms in conjunction with optimized biochemical methods. Compared to traditional methods, this combination offers superior sensitivity, improved coverage, integrated testing, and faster turnaround.

For more information including details on Invitae’s method, please read our white paper.

How has Invitae validated this method?
To clinically evaluate Invitae’s approach, DNA specimens were collected from a representative population of approximately 1,000 patients who had previously received testing using traditional technologies (Lincoln 2015). An additional set of 118 known positive specimens that carried del/dup events in genes across the Invitae test menu was also collected. The studies found 100% sensitivity (zero false negatives) for del/dup events.

Invitae has performed del/dup testing in over 143,000 individuals, finding 2,096 pathogenic del/dup events across 230 genes confirmed using a secondary assay (Truty 2018, in press). This prevalence fits expectations. About one-third of these events impact only a single exon or have breakpoints within an exon, further demonstrating Invitae’s sensitivity to events that are challenging for traditional del/dup approaches.

Test your testing providers
We encourage you to test all your testing providers by asking:

  • Does the lab include del/dup testing automatically on all panels? If not, can you order it separately?
  • What methodology does the lab use?
  • Is there extra cost associated with del/dup testing?
  • If ordered as a reflex test, how much will this increase time to diagnosis?
  • Are there any gaps in coverage in the genes of interest to you?

If you have any questions about Invitae’s approach to deletion and duplication detection—or about our overall dedication to high-quality testing—please don’t hesitate to contact Client Services. We look forward to hearing from you.

This blog post was originally posted on March 1, 2017, and updated with new data on May 16, 2018.