About

What is the Medical Exome?

The human exome is the part of our DNA (our genome) that contains the protein-coding regions (exons) of our ~22,000 genes. It is estimated to make up approximately 1-2% of the genome, and to contain approximately 85% of pathogenic variants (mutations) known to cause disease. The Medical Exome test (i.e., whole exome sequencing or WES) is a sequencing test that covers ~98% of the exome. Exome sequencing provides >98% coverage of the ~22,000 human genes, with a mean read depth of 100X.

The Medical Exome has enhanced coverage (up to 100% coverage ≥20X) of the ~5300 genes known to be associated with disease. It also includes coverage of curated deep intronic and promoter pathogenic variants, and breakpoint baits spanning common deletion events (e.g., Krabbe disease 30kb deletion) commonly undetected by other exome sequencing tests. This coverage is twice the number of genes with complete coverage than is offered by competitors, making it the most comprehensive exome sequencing test available. The Medical Exome also includes selected class 1A pharmacogenetic targets.

The Medical Exome can be ordered with the Exome Slice Option, which allows clinicians to choose any gene panel relevant to the patient’s phenotype to ensure coverage of ALL exons of those genes, at no additional cost. Medical Exome sequence data without interpretation is also available as raw data files for clinical or research purposes.

Medical Exome

Why perform Medical Exome testing?

  • Medical Exome testing is meant to provide an answer faster by looking at the entire Exome at one time vs. a single gene, or set of genes, over a longer period of time.
  • Studies show that Medical Exome testing is superior to the current tiered approach of testing, and identifies pathogenic variants in ~28% of cases, drastically shortening the Diagnostic Odyssey experienced by many individuals with genetic disease and their families.

When is Medical Exome testing useful?

Medical Exome testing is helpful in the diagnosis of an affected individual when:

  • The patient’s symptoms or family history suggest a genetic etiology but does not correspond with a specific genetic disorder.
  • The patient has symptoms of a well-defined genetic disorder that is caused by multiple genes (genetic heterogeneity) for which a multi-gene panel is not clinically available.
  • The patient likely has a genetic disorder but previous clinical genetic testing did not yield a genetic diagnosis.
  • The patient’s clinical presentation is unclear/atypical and there are multiple genetic conditions in the differential diagnosis.

Why perform TRIO Medical Exome testing?

“TRIO” testing refers to testing the patient (aka proband) plus the patient’s biological parents. Testing all three family members at the same time can often help in interpreting variants found in the patient by determining if they came from the parents, and, if so, which parent. Testing the proband alone may lead to recommendations to test the parents for the variants found in the patient later.

What options are available for Medical Exome testing?

Test CodeTest DescriptionPatientCoverageTurnaround timeData Interpretation and Medical Report
EXOMEMedical Exome, with interpretation (one sample)Proband only100x4 weeks
EXOMETECHMedical Exome, no interpretation (one sample)Proband only100x14 days
EXOMETRIOMedical Exome, with interpretation (three samples)Proband + Parents100x4 weeks
EXOMETRIOTECHMedical Exome, no interpretation (three samples)Proband + Parents100x14 days
EXOMESTATMedical Exome, with interpretation (one sample) STATProband only100x7-10 days
EXOMESTATPLUSMedical Exome, with interpretation plus StepOne® Biochemical ProfileProband only100x7-10 days
EXOMETECHSTATMedical Exome, no interpretation (one sample) STATProband only100x7-10 days
EXOMETRIOSTATMedical Exome, with interpretation (three samples) STATProband + Parents100x7-10 days
EXOMETRIOSTATPLUSMedical Exome, with interpretation (three samples) STAT plus StepOne® Biochemical ProfileProband + Parents100x7-10 days
EXOMETRIOTECHSTATMedical Exome, no interpretation (three samples) STATProband + Parents100x7-10 days

TAT for StepOne is 3 calendar days. Click here to see StepOne details.

Additional Family Member can be ordered. However, the Medical Exome Trio should be ordered first or at the same time as the additional family members. 
SAN - Sanger Confirmation Only
SANINT - Sanger Confirmation and Interpretation Only
REANAL - Medical Exome: Reanalysis and Reinterpretation (requires submission of clinical report)

Who can order the Medical Exome?
Medical Exome testing can only be ordered by a physician and results will only be reported to a physician.

  • If you are a physician, please download the Medical Exome Requisition Form. Fully complete the requisition form and Informed Consent form, including signatures of the physician and patient. Return forms with your patient’s sample.
  • If you are a patient, please download the Medical Exome Requisition Form. Bring form to your physician to fully complete and sign. Your signature is also required. If appropriate, your physician will collect your sample and send to PerkinElmer Genetics for testing.

How to Order

Specimen Requirements

For Medical Exome testing, samples are required from the proband (i.e., patient). For Medical Exome TRIOs, samples are required from proband and both biological parents. For other biological relatives, please contact PerkinElmer Genetics for more information. Please submit all samples at the same time.

Preferred Sample Types:

  • Saliva (Please note, the StepOne® biochemical profile cannot be performed on saliva samples)
  • Whole Blood (Please note, the StepOne biochemical profile cannot be performed on whole blood samples)
  • Dried Blood Spots (DBS)(Please note, DBS samples are needed for StepOne biochemical profile)

To order a PerkinElmer Genetics sample collection pack, please submit an order form by clicking here. Or call Toll Free: 1-866-463-6436.

Please contact the lab before submitting any other specimen type. For other sample types, please find more details by clicking here.

Special Instructions

Please submit medical records or clinical summary notes, a requisition form and a signed informed consent form when ordering Medical Exome testing. Testing will not be initiated until these documents are received. See below link to download the Medical Exome test requisition form and informed consent form:

Who can order the Medical Exome?
Medical Exome testing can only be ordered by a physician and results will only be reported to a physician.

  • If you are a physician, please download the Medical Exome Requisition Form. Fully complete the requisition form and Informed Consent form, including signatures of the physician and patient. Return forms with your patient’s sample.
  • If you are a patient, please download the Medical Exome Requisition Form. Bring form to your physician to fully complete and sign. Your signature is also required. If appropriate, your physician will collect your sample and send to PerkinElmer Genetics for testing.

Download Medical Exome Requisition Form

Methodology

The Medical Exome is performed on genomic DNA using the Illumina NovaSeq system, with 2x150bp basepair (bp) paired-end reads and an average coverage of 100X in the target region. (The target region includes the exon and 10 bp of flanking intronic region, plus other predefined regions of interest.) The DNA sequence is mapped to, and analyzed in, comparison with the published human genome build UCSC hg19 reference sequence. The targeted coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the depth of coverage and data quality threshold values. The PerkinElmer proprietary Medical Exome bioinformatics analysis pipeline is used to compare sequence changes in the individual being tested to the reference sequence. All potential positive sequence variants in the proband are confirmed by conventional di-deoxy DNA sequence analysis (Sanger sequencing) using a separate DNA isolation.

The Medical Exome also features the Exome Slice Option, which allows clinicians to choose a PerkinElmer Genetics gene panel relevant to the patient’s phenotype to ensure coverage of ALL exons in those genes, at no additional cost.

An interpretation service is offered for exomes sequenced outside PerkinElmer Genetics, in either clinical or core laboratories.

Detection

The Medical Exome provides a genetic diagnosis for approximately 28% of patients undergoing testing.

FAQs

What is the Medical Exome?
The Medical Exome targets the protein-coding regions (exons) of the approximately 22,000 genes in the genome (the exome). It is a powerful diagnostic tool, providing a definitive diagnosis in ~25-30% of patients.

When is Medical Exome testing useful?
The Medical Exome is useful when:

  • The patient’s symptoms or family history suggest a genetic etiology but does not correspond with a specific genetic disorder.
  • The patient has symptoms of a well-defined genetic disorder that is caused by multiple genes (genetic heterogeneity) for which a multi-gene panel is not clinically available.
  • The patient likely has a genetic disorder but previous clinical genetic testing did not yield a genetic diagnosis.
  • The patient’s clinical presentation is unclear/atypical and there are multiple genetic conditions in the differential diagnosis.

How long does it take to get my patient’s results for the Medical Exome?
The turnaround time (TAT) is measured from sample receipt to delivery of the results report. This assumes that all required paperwork is completed fully and accurately at the time of sample submission. The TAT for the Medical Exome is 28 calendar days.
Documents needed are:

Can I get my Medical Exome results faster than the stated turnaround time (TAT)?
Arrangements may be made for results to be returned STAT if required for urgent medical management. Medical interpretation and report may be provided STAT within 7-10 calendar days after the sample has been sequenced. There is an additional charge for STAT orders. For pricing, please email PerkinElmer Genetics or call us at 866-463-6436. Please indicate STAT testing by checking the Medical Genome STAT testing in the Whole Exome Sequencing Requisition Form.
STAT options include:

  • EXOMESTAT: Medical Exome, with interpretation STAT
  • EXOMESTATPLUS: Medical Exome, with interpretation STAT plus StepOne® Biochemical Profile
  • EXOMETECHSTAT: Medical Exome, no interpretation STAT
  • EXOMETRIOSTAT: Medical Exome Trio, with interpretation STAT
  • EXNOMETRIOSTATPLUS: Medical Exome Trio, with interpretation STAT plus StepOne® Biochemical Profile
  • EXOMETRIOTECHSTAT: Medical Exome Trio, no interpretation STAT

Can I submit a sample for the Medical Exome without an order from a health care provider?
No, Medical Exome testing must be ordered by a physician and results will only be reported to a physician.

What specimens are acceptable for Medical Exome testing?
Strongly preferred sample types for Medical Exome testing are dried blood spot (DBS), saliva, and whole blood (EDTA/purple top tube).

What is the price for Medical Exome sequencing?
For pricing, please email PerkinElmer Genetics or call us at 866-463-6436.

Does PerkinElmer Genetics accept insurance or file for insurance directly?
At this time, PerkinElmer Genetics accepts only institution bill accounts or testing paid in-full by the patient at the time of testing.

Does PerkinElmer Genetics offer Medical Exome sequencing without medical interpretation?

  • Yes, we offer sequencing of the patient sample without medical interpretation.
  • To obtain sequencing results only, please indicate on the Whole Exome Sequencing Requisition Form
  • Sequencing only options include:
    • EXOMETECH: Medical Exome, no interpretation
    • EXOMETRIOTECH: Medical Exome Trio, no interpretation
    • EXOMETECHSTAT: Medical Exome, no interpretation STAT
    • EXOMETRIOTECHSTAT: Medical Exome Trio, no interpretation STAT

Does PerkinElmer Genetics offer reanalysis of Medical Exome data and what is the cost?

  • Yes, we offer reanalysis of exome data.
  • We recommend waiting 6-12 months after the initial test was reported to allow additional curation of new research/clinical information.
  • Turnaround time: 7-14 calendar days
  • For pricing, please email PerkinElmer Genetics or call us at 866-463-6436.

How much of the exome is covered with the Medical Exome test?
The Medical Exome covers ~92% of the exome

Can we have access to the raw data? E.g., BAM, FastQ, VCF?
The raw data generated can be requested by the ordering health care provider.

What is reported in Medical Exome testing?

  • Variants that are known to be pathogenic or for which the laboratory has sufficient evidence suggesting pathogenicity in a gene that is suspected to cause the patient’s signs/symptoms.
  • Predicted mutation(s) in a gene, which is potentially related to the phenotype but for which a specific clinical phenotype has not been previously well defined.
  • Variants of uncertain clinical significance in genes known to be associated with disease and genes not know currently associated with a disease (new genes) related to the patient’s phenotype.
  • Variants that are pathogenic or for which the laboratory has sufficient evidence suggesting pathogenicity in a gene that is medically significant but unrelated to the patient’s presenting symptoms, unless the patient or parent/guardian declines this information.

Are there any genes/regions that will not be reported?

  • A fraction (~10%) of the exome cannot be sequenced to accurately determine if a pathogenic variant is present. Therefore, pathogenic variants in these regions will not be detected by this analysis.
  • NGS cannot accurately sequence repetitive regions, such as trinucleotide repeats. This means that NGS cannot provide data on regions such as the fragile X syndrome repeat region, the Huntington disease repeat region, or the myotonic dystrophy repeat region.
  • Results from the Testing may indicate that additional testing, such as full gene sequencing to complete exons with poor coverage or deletion/duplication analysis, is recommended.
  • Genetic changes identified may not necessarily predict the prognosis or severity of disease and it is possible that the genetic change may not affect management or treatment.
  • Mitochondrial genome mutations, genes with pseudogenes, and epigenetic defects may not be detected by this test.

How does PerkinElmer Genetics handle reporting of incidental findings?
Adult patients and family members are given options in the informed consent form to indicate what type of results should be delivered. Options to opt-in for any of the following are provided:

  • Pharmacogenetic variants: Pharmacogenetic variants are changes in the DNA that do not cause a disease but may be related to how your body processes certain medications, such as chemotherapy drugs, antipyretics, antidepressants, anticoagulants, and others. These variants may not be important to you if you are not taking the medications involved, but may tell you how well the medications will work or if you will have side effects if you do take the medications now or in the future.
  • Carrier Status for Autosomal Recessive Conditions (ex. cystic fibrosis) A recessive condition is one in which two pathogenic variants in the same gene are required in order to show symptoms of the disease (one variant is inherited from each parent). Someone who has only one pathogenic variant does not show symptoms and is called a carrier. However, if we find a pathogenic variant in a recessive gene that is related to the patient's disease, we will report it as a diagnostic finding. Further testing may be necessary to look for a second pathogenic variant in that gene not identified by WES. You can choose whether or not you want us to report carrier status in genes that are not related to the patient's disease. The Testing is not designed to be a comprehensive carrier test. We are unable to guarantee that all conditions for which the individual is a carrier will be determined by the Testing. An individual may be a carrier for a condition in which there was little or no coverage in the Testing and therefore will not be detected. Additional carrier testing for reproductive purposes should be discussed with your doctor or genetic counselor.
  • Diagnostic findings in adult onset medically-actionable disorders not related to disease: Medically-actionable conditions are those for which there is currently recommended treatment or preventative actions that can be taken to reduce the risk of developing the disease. An example would be hereditary cancer syndromes such as Lynch syndrome. We are unable to guarantee that the Testing will find all adult onset medically-actionable conditions for which the individual has a pathogenic variant. An individual may have a pathogenic variant for a condition in which there was little or no coverage in the Testing and therefore will not be detected. Additional testing for health purposes should be discussed with your doctor or genetic counselor.
  • Diagnostic findings in adult onset currently medically non-actionable disorders not related to disease: Conditions that are not currently medically-actionable do not have recommended treatment or preventative measures. An example would be Alzheimer's disease. We are unable to guarantee that the Testing will find all adult onset medically non-actionable conditions for which the individual has a pathogenic variant. An individual may have a pathogenic variant for a condition in which there was little or no coverage in the Testing and therefore will not be detected. Additional testing for health purposes should be discussed with your doctor or genetic counselor.

Will PerkinElmer Genetics Medical Exome test detect mitochondrial disease?

  • Mitochondrial diseases can be caused by mutations in either the mitochondrial genome (a small circular chromosome found within the mitochondria) or by mutations in the nuclear genome (on the chromosomes found in the nucleus). Whole exome sequencing is typically done in such a way that only the exons in the nuclear genome are captured and fully sequenced, and thus, will identify most but not all of the mutations associated with mitochondrial disease.
  • We are not capturing the entire mitochondrial genome as, with our experience, the yield is less than 1% and has low clinical utility.
  • Our assay does, however, include common point mutations in the mitochondrial genome associated with diseases such as LHON, MERRF, and NARP.
  • If you would like to discuss mitochondrial genome sequencing, please email PerkinElmer Genetics or call us at 866-463-6436 for more information.

Do you perform confirmation of mutations that are detected by the Medical Exome?
Yes.

What sequencing platform does PerkinElmer Genetics use for the Medical Exome test?
PerkinElmer Genetics uses the latest sequencing platforms from Illumina. We have a variety of MiSeq®, HiSeq®, and NovaSeq instruments that can be used to generate data for the Medical Exome.

What exome capture solution does PerkinElmer Genetics use for the Medical Exome test?
PerkinElmer Genetics is using Agilent SureSelect capture reagents.

How do I order sample collection kits?

  • DBS collection packs can be ordered through customer service or via an email.
  • Saliva or whole blood collection packs are currently not available. Once they become available they can be ordered in the same manner.

References

  1. ACMG Board of Directors. ACMG Policy Statement: Points to consider in the clinical application of genomic sequencing. Genet Med. 2012;14(8):759-76.
  2. Taylor, J et. al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nature Genetics 47, 717–726 (2015)
  3. Gilissen C., Hehir-Kwa J.Y., Thung D.T. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511:344–347
  4. Belkadi A., Bolze A., Itan Y. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 2015; 112:5473–5478
  5. Saunders C.J., Miller N.A., Soden S.E. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012; 4:154
  6. Dewey F.E., Grove M.E., Pan C. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014; 311:1035–1045
  7. The 100,000 Genomes Project. 2014. Accessed January 10, 2015.
  8. Petersen BS, et. al. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet. 2017 Feb 14;18(1):14.
  9. Hegde M, et. al. Development and Validation of Clinical Whole-Exome and Whole-Genome Sequencing for Detection of Germline Variants in Inherited Disease. Arch Pathol Lab Med. 2017 Mar 31.
  10. Zornitza, S, Schofield, D. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genetics in Medicine. 2017. doi:10.1038/gim.2016.221
  11. Lupski, J et. al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010 April 1; 362(13): 1181–1191
  12. Biesecker, LG and Green, RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370:2418-25.
  13. Worthey, EA et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 2011. 13(3):255-262.
  14. Yang, Y et. al. Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders. N Engl J Med. 2013; 369:1502-1511.
  15. Visser, L et. al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017; Online 23 March 2017
  16. Stavropoulos, DJ et al. Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine. Genomic Medicine. 2016. 1, 15012