Exome

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The Invitae Boosted Exome is a customized analysis of the human exome based on a combination of the patient’s clinical presentation and the variants found within his/her exome.

Our exome combines rigorous bioinformatics with detailed phenotypic and clinical information to yield relevant information for your patient.

We will analyze:

After sequencing the exome, variants identified that meet the following criteria will be interpreted according to American College of Medical Genetics and Genomics criteria:

  1. All variants in genes specifically requested in the order and which are covered by the assay, plus
  2. Variants detected in genes:
    • that are likely to be disruptive (e.g., cause premature truncation events, interfere with canonical splice sites, initiator, frameshift, or whole-exon deletions), or
    • for which there are two variants detected in a single gene associated with a condition that is autosomal recessive, plus
  3. Variants detected in genes associated with Mendelian conditions that correspond to the patient’s presentation that:
    • are reported to cause disease in publications but are absent in frequency databases
  4. For a trio analysis (when samples from both parents are provided for analysis),
    • variants shown to be de novo in the patient, or
    • variants segregating as X-linked, or
    • autosomal recessive.

We will report:

Of the variants interpreted, only variants that are deemed likely to have medical implications for the patient (e.g., pathogenic/likely pathogenic, or highly suspicious variants of uncertain significance) will be reported.

In addition, a proband and/or parents may choose to have an additional analysis for secondary findings as recommended by the American College of Medical Genetics (ACMG59, Kalia et al 2017) at no additional charge. A separate report for each individual will be generated evaluating pathogenic/likely pathogenic variants in this set of 59 genes. The decision of a proband and each family member to opt in to this additional analysis is required at the time the test is ordered by a clinician. The additional reports evaluating the ACMG59 genes will be released as companion reports at the time the clinical exome report is released.

The Invitae Boosted Exome detects single nucleotide variants, indels less than 50 bp, and intragenic copy number variants across >18,000 genes. However, in contrast to Invitae’s gene panel sequencing where single-exon del/dups are detected, the greater variability in depth of coverage across an exome permits reliable detection of del/dups spanning 4 exons or more with high confidence; smaller events may be detected and will be reported when sufficient resolution exists.

To ensure high sensitivity and specificity, the exome is sequenced to an average depth of 150x (per base). Over 18,000 genes of the mappable exome are called at high quality (depth ≥20x). Joint calling is performed to maximize sensitivity.

The assay is not intended to detect large copy number variations (cytogenetic events), indels >50 bp, or mosaic/somatic events constituting less than 20% of the total calls in that tissue. The assay does not detect variants in mitochondrial DNA.

  1. All variants in genes specifically requested in the order and which are covered by the assay, plus
  2. Variants detected in genes:
    • that are likely to be disruptive (e.g., cause premature truncation events, interfere with canonical splice sites, initiator, frameshift, or whole-exon deletions), or
    • for which there are two variants detected in a single gene associated with a condition that is autosomal recessive, plus
  3. Variants detected in genes associated with Mendelian conditions that correspond to the patient’s presentation that:
    • are reported to cause disease in publications but are absent in frequency databases

Of the variants interpreted, only variants that are deemed likely to have medical implications for the patient (e.g., pathogenic/likely pathogenic or highly suspicious variants of uncertain significance) will be reported.

Using orthogonal technologies, Invitae confirms all clinically significant findings (e.g., pathogenic or likely pathogenic and sufficient to explain the patient’s phenotype) that do not meet stringent NGS quality metrics. The confirmation techniques we use include Sanger sequencing, PacBio sequencing of circularized amplicons, array comparative genome hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA).

The Invitae Boosted Exome is not intended for research or gene discovery.

This test is only appropriate for identifying conditions with Mendelian (single-gene) etiologies; complex conditions such as lupus, type 2 diabetes, psychiatric disorders, or fibromyalgia are examples of conditions in which genetic variants may affect risk, but are not appropriately evaluated with the Invitae Boosted Exome. This test is not indicated for hereditary cancer analysis or individuals with no personal history of disease.

Currently, this analysis does not include detection of large cytogenetic events, mitochondrial DNA variants, or methylation/imprinting abnormalities. Additionally, this test will not not detect triplet repeats and may not detect mosaic/somatic variants.

Sequencing parametersVariants interpretedReport provided
Proband
  • Average 150x coverage (per base) across all exons with >99.4% of reportable exons covered at ≥20x
  • Invitae’s high-quality variant calling detects:
    • single nucleotide variants
    • small deletions/insertions <50 bp
    • intragenic copy number variants*
Trio
  • Exome sequencing of all three samples with joint calling
Proband
  • Variants absent in frequency databases but for which there are publications
  • Hemizygous, presumed compound heterozygous, and homozygous variants, plus
  • Variants predicted to cause loss of function
Trio
  • Everything interpreted in the proband, plus
  • Variants segregating as X-linked or autosomal recessive (in trans), plus
  • De novo variants
Proband
  • A clinical summary describing relevant findings
  • Detailed information including:
    • list of analyzed genes
    • pathogenic and likely pathogenic variants related to the indication for testing, and some variants of uncertain significance that follow an appropriate inheritance mode and closely match the patient’s phenotype
    • description of relevant variants with citations
    • in-depth description of technical coverage
  • Optional secondary findings report (based on the latest ACMG recommendations) for all sequenced individuals
Trio
  • Inheritance patterns associated with all reported variants

*In contrast to Invitae’s gene panel sequencing where single-exon del/dups are detected, the greater variability in depth of coverage across an exome permits reliable detection of del/dups spanning 4 exons or more with high confidence; smaller events may be detected and will be reported when sufficient resolution exists.

The Invitae Boosted Exome can only be ordered through our online portal. Paper requisitions are not available. To order the Invitae Boosted Exome, log into your online Invitae account or, if you are new to our site, create an account. Once you’ve logged in, follow the prompts to “Start an Order” and follow the detailed instructions guiding you through the process. Test selection, demographic information, clinical information, and consent are all collected via our online ordering portal.

Please note:

  • It is important that you complete and submit your online order prior to shipping your patient specimen(s).
  • Ensure that all specimens arrive within 30 days of placing the order.
  • Please upload relevant test results only (e.g., microarray/cytogenetic results, biochemical test results, prior molecular test results, MRI reports, EMG/NCV). Please do not upload full medical records or clinical consult notes at this time.
  • We accept the following sample types: blood, saliva, and assisted saliva. Previously extracted DNA is not accepted at this time.
  • We can send specimen collection kits to your office or patient’s home free of charge; we also offer a mobile phlebotomy service in the US and Canada. Visit the Request a kit page to learn more.
  • If you are ordering for a trio, please request three collection kits; for a duo, please request two kits; and for proband only, please request one kit.

A consent form is available in the online ordering portal; however, this form does not need to be returned with your specimen. Your attestation during the ordering process states that the patient has been consented and is sufficient for us to proceed with testing. Our consent form or another consent form of your choice that is substantially similar to Invitae’s should be kept with your patient’s medical records at your site.

Consent for the Invitae Boosted Exome provides patients and parents the choice to opt in or out of receiving information on the actionable secondary findings that have been recommended by the ACMG. In the course of carrying out a rigorous analysis of exome sequence, we may incidentally discover genetic changes that are of medical importance but are not directly relevant to the initial reason for the exome testing. We will include such incidental findings in our primary report, with an appropriate explanation, if they have significant healthcare implications for the proband as determined using published recommendations on evaluating clinical actionability (Berg et al., 2013, 2016). In particular, we will not report any incidental findings associated with adult-onset disorders for which there are no interventions available. (Please note that such incidental findings are distinct from those in genes on the ACMG “secondary” findings list for which there is a recommendation that all patients be given the option to have these genes examined deliberately.)

When ordering exome, the most informative results are generally derived from a trio, which includes the patient, biological mother, and biological father. Duos (patient and one biological parent) as well as proband-only specimens are also accepted.

The Invitae Boosted Exome provides patients and parents the choice to opt in or out of receiving information on the actionable secondary findings that have been recommended by the ACMG. All individuals who opt in for the secondary findings will receive a separate report.

When placing an order for an exome, Invitae provides an online phenotype tool that has been developed to allow clinicians to quickly and qualitatively select their patient’s phenotype from various drop-down menus. These phenotypes are derived from the Human Phenotype Ontology Project and then analyzed against HGMD, ClinVar, OMIM, and DisGeNet to generate a list of possible genes associated with the patient’s phenotype.

When deciding which term(s) to include, please be sure to include all that match your patient’s presentation, even when the terms may be redundant. Please note that, once a term is selected, more detailed information can be provided in the text boxes. It is very important that we receive a detailed description of the patient’s phenotype so we can appropriately customize our analysis and determine what is reported.

Prior to ordering the Invitae Boosted Exome, clinicians can use our Gene coverage search tool to see how well specific gene(s) of interest are covered by the assay. During the online ordering process, the clinician is also able to indicate if there are particular genes of interest to ensure that those are included in the analysis.

When a trio is ordered, parental specimens are already utilized for variant resolution as part of the analysis. However, if a proband-only or duo exome is ordered and the family later wants to establish inheritance from one or both parents, the testing is available for $200 per gene, per person. Family variant testing is also available to other family members.

During the testing process, the submitted specimen is typically exhausted and therefore is not available after exome sequencing for additional testing. If there is a concern regarding this, consider extracting additional DNA to be held at your site or at a DNA banking facility.

Insurance billing
Insurance billing is available for exome testing. We will conduct a Benefits Investigation (BI) on every order and contact the patient if their out-of-pocket responsibility is greater than $100 or if the authorization request is denied. We will inform the patient of their options, including payment plans, our patient assistance program, patient pre-pay, and canceling the test. If the patient opts to cancel the test we will contact the clinician.

We will manage the prior authorization process.

We do not accept Medicare or managed Medicare for exome at this time.

We do not accept Medicaid or managed Medicaid for exome orders, but other payment options may be applicable. Visit the Support Center for more information.

Institutional billing
We will work with your institution to set up a contract if one is not already in place, and we encourage referring institutions (i.e., clinics, hospitals, labs, and private practices) to set up contracts with us in advance.

Invitae will never charge an institution more than the published exome price of $2,500 (trio/duo) or $1,250 (proband only).

Please contact Client Services for more information.

Patient pay
Genetic testing should be affordable and accessible to anyone who needs it. For exome testing, Invitae offers a patient-pay price:

  • Invitae Boosted Exome Trio or Duo: $2,500
  • Invitae Boosted Exome Proband-Only: $1,250

In addition, Invitae offers a payment plan to help make exome testing more affordable. Under the plan, patients can pay 50% of the exome price up front, and then make interest-free payments on the balance over 12 months. Please contact Client Services for more information or to be enrolled in the payment plan.

Patient assistance
Invitae also offers financial assistance programs based on poverty guidelines, assessed on an individual basis. Please contact the Billing Department for more information.

Learn more about these payment options on the Billing webpage.

The Invitae Boosted Exome report is designed to summarize the most salient information, focusing on variants that are likely to have medical implications for the patient. These include pathogenic and likely pathogenic variants related to the indication for testing and variants of uncertain significance that follow an appropriate inheritance mode and/or where the condition associated with a gene has overlapping features that match the patient’s phenotype. A clinical summary describing the relevant findings is followed by a detailed description of reportable variants that are found within genes associated with Mendelian conditions that correspond to the patient’s presentation and additional genes you indicate, through analyses for truncating and loss of function variants, and through analyses of inheritance patterns

Variants fulfilling reportable criteria will appear with a full variant description and citations. For trios, inheritance patterns of variants will be indicated.

If the proband and/or family chooses to opt in to the ACMG59 secondary findings companion analysis, each individual will receive a separate report for those analyses. The decision to opt in or opt out of this additional, separate analysis should be discussed and decided on with the ordering clinician at the time the exome order is placed.

Sample reports are available. Please contact Client Services.

The Invitae Boosted Exome analyzes nuclear genes only. Nuclear genes that affect mitochondrial function will be analyzed, but mitochondrial DNA is not included in the analysis.

In the course of carrying out a rigorous analysis of exome sequence, we may incidentally discover genetic changes that are of medical importance but are not directly relevant to the initial reason for the exome testing. We will include such incidental findings in our primary report, with an appropriate explanation, if they have significant healthcare implications for the proband as determined using published recommendations on evaluating clinical actionability (Berg et al., 2013, 2016). In particular, we will not report any incidental findings associated with adult-onset disorders for which there are no interventions available. (Please note that such incidental findings are distinct from those in genes on the ACMG “secondary” findings list for which there is a recommendation that all patients be given the option to have these genes examined deliberately.)

The American College of Medical Genetics (ACMG) has recommended a list of genes to be analyzed simultaneously when whole exome or whole genome sequencing is ordered. These genes have been deemed medically actionable, and clinical and management guidelines exist for their associated conditions. Any variants in these genes interpreted as pathogenic or likely pathogenic will be reported out in an optional secondary findings report. Patients and sequenced family members are able to opt in or out of the secondary findings during the ordering process. All individuals who opt in for the secondary findings will receive a unique RQ number in the online portal and a separate report.

As knowledge increases, variants are occasionally reclassified. When a variant that was reported as uncertain is now considered actionable (pathogenic/likely pathogenic) or a variation thought to be actionable is now considered uncertain or benign, we will issue an amended report to the ordering physician. Please emphasize to your patient the importance of maintaining up-to-date contact information with your practice so that when you receive an amended report, you are able to communicate the new information to your patient.

Full re-analysis of exome results will be coming soon.

Whole exome sequencing is a genetic test that uses next-generation sequencing technology to analyze the coding regions of approximately 20,000 genes. This test identifies DNA changes in an attempt to pinpoint an individual’s genetic diagnosis. These coding regions are called exons and all of the exons together are called an exome. It is estimated that the vast majority of disease-causing DNA changes are found in the exons, which is why the test focuses on these regions. The test also includes analysis of approximately 10 base pairs of DNA into the introns of each gene. While the introns are considered to be non-coding, changes to these regions can alter the expression and function of the exons, thereby causing disease.

Exome sequencing is often ordered when individuals present with complex, often syndromic symptoms that have a suspected genetic etiology. Exome sequencing offers an efficient method to target approximately 20,000 genes at once, thus providing a cost-effective, timely tool to assess multiple genes at once. In addition, it can provide a means to determine the diagnosis for patients who have undergone other forms of testing with no informative results. Results from exome sequencing can directly inform medical treatment, determine recurrence risks for patients and family members, and end the need for additional costly or invasive tests and procedures.

In contrast, when a patient has a well-defined phenotype that is highly suggestive of a single, known genetic condition, single-gene or panel testing is typically indicated. If you would like assistance in determining whether exome sequencing is the best choice over single-gene testing or a gene panel for your patient, we are happy to provide Clinical Consult Services.