Exome

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The Invitae 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 revolutionary analysis and interpretation process combines automated gene and variant curation with expert evaluation for fast, reproducible, and accurate exome interpretation.

Invitae’s medical team consists of PhD scientists, certified genetic counselors, and board-certified laboratory geneticists with extensive experience performing clinical exome sequencing.

Analysis and interpretation with Moon
Artificial intelligence (AI)-powered software weighs clinical and genetic information to identify the variants most relevant to each patient’s case.

  • Moon ranks potential causative variants based on weighted parameters including patient phenotype, gene-disease associations, predicted molecular effects, and family information.
  • Moon provides the exome analysis team a short list of potential positives sifted from the comprehensive exome sequence data. These variants are reviewed by our medical team and then clinically evaluated within our proven variant-interpretation framework (Sherloc).

Gene-disease curation with Apollo

  • Apollo is an AI-powered tool that uses natural language processing to perform daily automated literature searches for new gene-disease relationships.
  • The information gathered is weighted to prioritize the phenotypic features most often observed with the disease and the results are manually curated and annotated by expert scientists and genetic counselors.
  • This continuously growing knowledge base integrates new scientific insights, guaranteeing a comprehensive and up-to-date analysis for every patient.

To ensure high sensitivity and specificity, the Invitae Exome is sequenced to an average depth of 150x per base and >99.4% of exons included in the assay are covered at ≥20x. When parental samples are submitted, joint calling is performed to maximize sensitivity.

The Invitae 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 panels where single-exon del/dups are detected, the greater variability in depth of coverage across an exome permits reliable detection of deletions and duplications spanning 4 exons or more with high confidence; smaller events may be detected and will be reported when sufficient resolution exists.

Using orthogonal technologies, Invitae confirms all clinically significant findings (e.g., pathogenic or likely pathogenic variants 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 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 the specimen. The assay does not detect variants in mitochondrial DNA.

The Invitae 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 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 detect triplet repeats and may not detect mosaic/somatic variants.

The Invitae Exome can only be ordered through our online portal. Paper requisitions are not available. To order the Invitae 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 including optional secondary findings analysis, 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 any relevant clinical notes and test results for the proband including previous genetic testing results, biochemical testing results, MRI reports, EMG/NCV reports, etc. Adequate clinical information is required for accurate and informative exome analysis.
  • We accept the following sample types: blood, saliva, assisted saliva, buccal swabs, and isolated DNA.
  • 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.

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.

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.

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 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 a non-sequenced family later wants to establish inheritance from one or both parents, familial variant testing is available for $200 per gene, per person. Family variant testing is also available to other family members. A paper requisition is required for exome-related familial variant testing.

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.

Invitae accepts Medicaid and managed Medicaid for exome orders placed in the states listed on this FAQ. For all other states, we offer a payment option where Invitae can client bill your practice or institution at a reduced rate; please contact Invitae for more information. No contract (LSA) is required.

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 Exome Trio or Duo: $2,500
  • Invitae 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.

Our team of exome experts aims to report clinically relevant variants that are classified as pathogenic, likely pathogenic, or variants of uncertain significance in genes with phenotypic overlap to the patient’s phenotype and inheritance patterns that match the known gene-disease association. In addition, Invitae will also report single pathogenic and likely pathogenic variants in autosomal recessive genes when there is strong clinical overlap or when clinical overlap is weaker but treatment is available or further testing may rule the disorder in/out.

Variants fulfilling our reporting criteria will appear with a full variant description and citations. For trios and duos, the presence or absence of variants in parents will be indicated.

If the proband and/or family chooses to opt-in to the secondary findings companion analysis, each individual will receive a separate report for those analyses.

Sample reports are available. Please contact Client Services.

The Invitae 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 the exome sequence, Invitae may incidentally discover genetic changes that are of medical importance but are not directly relevant to the primary reason for the exome testing. If Invitae identifies an incidental finding, we will report them in the primary exome report, with an appropriate explanation. Invitae will not report any incidental findings associated with adult-onset neurodegenerative disorders for which there are no interventions available. In keeping with medical practice best standards, incidental findings are considered to fall within Invitae’s duty to notify policy, and there is no option to opt-out, even if the finding happens to fall within one of the ACMG secondary findings genes.

Example of an incidental finding we would report: Pathogenic variant in the FLCN gene associated with Birt-Hogg-Dube syndrome, a hereditary cancer predisposition syndrome associated with benign hamartomatous skin lesions, benign and malignant kidney neoplasms, and lung cysts leading to spontaneous pneumothorax.

Example of an incidental finding we would NOT report: Pathogenic variant in the PSEN1 gene associated with Alzheimer’s disease. This finding would not be reported (unless the proband had a cognitive or memory disorder) because it is an adult-onset neurodegenerative disorder with no current interventions available.

All individuals undergoing exome sequencing may choose to have an additional deliberate analysis for secondary findings as recommended by the American College of Medical Genetics (Kalia 2017) at no additional charge. A separate report for each individual will be generated for this set of 59 genes, and any variants interpreted as pathogenic and likely pathogenic will be reported. 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 these 59 genes will be released as independent companion reports that are released separately.

Case-level reanalysis is a re-review of all variants in the case, both reported and unreported, in the context of the patient’s phenotype. Routine case-level reanalysis is included in the cost of the test and performed every 6 months for a minimum of 3 years. In addition, provider-initiated reanalysis is also available upon request.

Variant-level reevaluation occurs when there are known variant upgrades/downgrades or a gene is now considered a disease gene. These cases are flagged internally based on changes to a specific variant or gene, then the corresponding cases are reviewed and reports are updated as necessary. Invitae has always offered variant-level reevaluation and will continue to offer this service.

It is important that providers maintain up-to-date contact information with Invitae so that when an amended report is issued Invitae is able to communicate updated results.

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 an 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.