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Order Guide: Exome Sequencing

General Information  Order ConsiderationsUtilization Management


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

What is exome sequencing?

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.


When is exome sequencing considered for a patient?

Exome sequencing is typically considered in the following circumstances:

  • To guide medical interventions (e.g., medications, other treatment or surveillance)
  • To inform prognosis (anticipatory guidance)
  • To provide information regarding recurrence risk (guide reproductive planning)
  • To end the diagnostic odyssey
  • When there is no alternative, more appropriate test


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Order Considerations

What important factors should be considered before ordering an exome?

The following questions provide a helpful framework when considering exome sequencing and its appropriateness for the individual:

  • Is there an alternate genetic or biochemical test that is more appropriate? For example, based on clinical symptoms, a single-gene test, chromosomal microarray, targeted panel or enzyme assay may have a higher diagnostic yield or effectively rule out the condition of interest. A referral to, or consult with an expert, such as a geneticist, should be considered if there are questions about alternate testing options.
  • Is the patient acutely ill and will results return in time to impact care (e.g. signs of decline or regression)? Arriving at a diagnosis more quickly for a critically ill infant in the NICU may warrant consideration of exome sequencing as the first-tier in testing.
  • Are there multiple individuals in the family with similar clinical features? Testing one individual may benefit many family members. Furthermore, testing many similarly affected individuals may yield more informative results.
  • Is there suspicion for a novel condition/gene? If the testing is being pursued to discover the first case of something, a research exome may be more appropriate because variants may be filtered and reported differently.
  • What is the benefit of pursuing testing now versus deferring until later? Consider that the test technology and interpretation of results are rapidly advancing and will improve; symptoms & family history may evolve to guide more targeted testing; the cost of testing will likely decrease; and available treatment options may increase.


When is it not appropriate to order exome sequencing?
  • When there would there be no change to the individual’s management regardless of the genetic test result.
  • When there has been no pre-test counseling for the individual (or legal guardian) regarding risks, benefits, and potential out of pocket costs of the genetic testing.
  • When the order is requested by a provider who may not have the appropriate training/expertise to select the optimal test and/or interpret the results. Generally, exome sequencing is best coordinated by geneticist or other specialist with genetics expertise. In addition, availability of a genetic counselor to provider pre- and post-testing counseling and assist with logistical aspects of test coordination is strongly recommended.

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General utilization management interventions & considerations

Utilization Management Techniques

Exome sequencing is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.

  • Establish a formulary for exome sequencing to limit ordering to a defined reference laboratory (or set of laboratories) to ensure quality of the test and improve ease of test coordination/logistics. This may also help with negotiating the best price.
  • Develop a Committee or at minimum an expert reviewer, and require that requests be reviewed prior to approval
  • Privilege exome sequence ordering to the experts. Due to the complex nature of exome sequencing, many institutions privilege this test to genetics providers only.


Provider and Patient Expectations

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.


Testing Approach
  • Reflex testing options: In some cases, it is more efficient and cost-effective to pursue a reflexive testing approach, starting with a targeted panel. Many reference laboratories have the option of running the whole exome, but masking the majority of genes and only reporting out on genes of interest (for instance, a defined subset of epilepsy genes or a customized panel). This may be defined by the reference laboratory and/or the ordering provider. If this analysis is negative, there may be an option to reflex to the whole exome.
  • Gene coverage by exome: When considering a targeted approach or whole exome sequencing, determining whether the gene(s) of most interest have good coverage on the platform.
  • Trio testing*: Although the cost of trio testing may be more than a proband-only exome, the use of trio testing is advantageous because it can reduce the rate of uncertain findings, add to the clinical sensitivity with regard to the interpretation of clinically novel genes, and it has been shown to increase the diagnostic yield of exome sequencing. In a recent study, the positive rate was 37.3% in patients undergoing trio analysis compared to 20.6% positive rate among proband-only exome sequencing.

    * 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.

Special/Additional Considerations

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.

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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:

  • Pre-counseling to provide clear information regarding the benefits, limitations and results of exome sequencing.
  • Clear documentation of medical rationale and necessity of exome sequencing, combined with insurance preauthorization for the testing to protect the patient/institution from avoidable financial liability.
  • Results communication plan established at time of test coordination, to include post-test counseling with a genetics provider. This is particularly important if there is concern that results may return after a patient is deceased. Multiple conversations may be required to clearly convey the results; starting with the disease-associated variants and then discussing secondary findings at a later visit is an approach taken at some institutions.

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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.

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.

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