Sign up now for a free account.
Announcing the New and Improved Concert Platform
Continue to Concert Genetics Website
Customer login
This order guide is powered by PLUGS®
Order Guide: Exome SequencingBackground
The intent of this document is to provide guidance on the appropriate coordination of exome sequencing. Exome sequencing is expensive, has a high chance of producing results that need to be interpreted by an expert, and is logistically challenging to coordinate (requires written consent, parental samples, and very detailed clinical history information). The following variables should be considered prior to ordering exome sequencing, and when in doubt, consider reviewing the order with an internal expert/manager/leader.
General Information
Clinical exome sequencing (CES) utilizes DNA-enrichment methods and massively parallel nucleotide sequencing to identify disease-associated, protein-coding variants throughout the human genome. The analysis is limited to the DNA sequence of coding regions (exons) and flanking intronic regions of the genome. Pathogenic variants that can be identified by this method include missense, nonsense, splice-site, and small deletions or insertions. However, clinical exome sequencing will typically miss certain classes of disease-causing variants, such as structural variants (translocations, inversions, etc.), copy-number variants, some mid-size insertions and deletions (ca. 10-500 bp), trinucleotide repeat expansion mutations, deeper intronic mutations, and lower-level mosaicism. Thus, in the choice of test methodology, the advantage of breadth of coverage must be balanced against the risk of missing disease-associated variants due to these technical limitations.
In addition to the possible identification of a variant directly related to the indication for testing, there is also the possibility of secondary findings (also called incidental results). Due to the complex nature of CES and potential challenges related to the results, a thoughtful testing approach is recommended.
Exome sequencing is typically considered in the following circumstances:
Order Considerations
The following questions provide a helpful framework when considering exome sequencing and its appropriateness for the individual:
General utilization management interventions & considerations
Exome sequencing is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.
Set clear expectations for providers regarding the use of this test and process for requesting and obtaining approval. Providers may feel that the patient came to them for evaluation, and genetic tests are their primary “tool”, so if a test isn’t ordered, they haven’t done their job. Similarly, it is critical for providers to set clear expectations for the patient or family, particularly if there are limits placed on when and how exome sequencing can be ordered.
* Trio testing typically involves sample collection from the proband and both parents. The laboratory may perform full exome sequencing for all three samples, or may give the option to perform full exome sequencing for the proband only, with targeted confirmation of variants using the parents’ samples.
In addition to the above considerations, there can be subtle aspects of a request for exome sequencing that are worth mentioning. For example, has the patient already had all imaging studies they would need if they were diagnosed with the suspected condition? (e.g. would it REALLY change the management of the patient now?) Does the provider already have a sense for intellect/prognosis? (e.g., intellect/prognosis in a 7 year old may be more clear than a 6 month old)
There are a variety of utilization management (UM) tools that can support appropriate ordering of exome sequencing. In addition, each case is unique and will require a balanced consideration of factors unique to exome sequencing.
Recommendations for responsible coordination of exome sequencing
Once exome sequencing has been established as the most appropriate test, the following recommendations are suggested as a responsible approach to test coordination:
References
American College of Medical Genetics Policy Statement: Points to Consider in the Clinical Application of Genomic Sequencing. Approved by the ACMG Board of Directors on March 27, 2012. http://www.acmg.net/StaticContent/PPG/Clinical_Application_of_Genomic_Sequencing.pdf
Atwal PS, Brennan ML, Cox R, et al. Clinical whole-exome sequencing: are we there yet? Genet Med 2014;16:717–719.
Baird G. The laboratory test utilization management toolbox. Biomedia Chemica 2014;24(2):223-234.
Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011 Sep 27;12(11):745-55.
Farwell KD, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2015 Jul;17(7):578-86.
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013 Jul;15(7):565-574.
Singleton AB. Exome sequencing: a transformative technology. Lancet Neurol. 2011 Oct;10(10):942-6.
Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med 2015 Jun;17(6):444-451.