ExomeNext

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Ambry's clinical diagnostic exome sequencing tests, ExomeNextTM, ExomeNext-RapidTM, ExomeNext-PrenatalTM, and ExomeNext-SelectTM are designed specifically for establishing neonatal, pediatric, adult-onset and prenatal genetic diagnoses. Ambry was the first to offer this technology commercially on a clinical basis.

Identifying and understanding a genetic diagnosis – especially when prior evaluations have not done so – allows for accurate disease identification and management. It also offers accurate genetic counseling for a family. Whole exome sequencing has successfully been used to identify both inherited and de novo causative gene mutations in a diverse variety of autosomal dominant, autosomal recessive, X-linked, and mitochondrial disorders. It is one of the most comprehensive tests to find the underlying genetic cause of a patient’s medical condition, and does so in a timely, cost-effective manner.

Ambry offers four options for clinical diagnostic exome sequencing. All exome sequencing tests use the same technology and bioinformatics pipeline. 

Our ExomeNext detection rate is 30% within characterized genetic etiologies and an additional 8% for candidate genetic etiologies  (Farwell KD, et al., Genetics in Medicine, 2014). ExomeNext-Rapid is available for cases when an expedited result is needed to immediately impact medical management (e.g. the NICU). Almost half of the neonatal samples Ambry has tested to date have identified a diagnosis
 

  ExomeNext ExomeNext-Rapid* ExomeNext-Prenatal* ExomeNext-Select
Turnaround time 8-12 weeks 8 days** 3-4 weeks 8-12 weeks
Number of genes analyzed*** up to ~20,000 up to ~20,000 up to ~20,000 up to 500
Mitochondrial genome Included Included Included No
Number of individuals sequenced Trio Trio Trio Proband Only
Family studies Included Included Included Included
Secondary Findings Results Included Included Included No
* Only institutional and cash billing are accepted for ExomeNext-Rapid and ExomeNext-Prenatal
** Verbal result provided within 8 days. Full report including mtDNA analysis, co-segregation analysis and Sanger confirmation provided within 14 days.
*** For all ExomeNext test options, analysis begins with characterized genes. If no relevant alterations are identified in characterized genes, analysis continues to candidate genes. Trio samples are required for candidate gene analysis.

 

ExomeNext/ExomeNext-Rapid/ExomeNext-Prenatal

ExomeNext is our clinical diagnostic exome sequencing test option using next generation sequencing methods targeted to the nuclear and mitochondrial (mtDNA) genomes. This, coupled with powerful bioinformatics (filtering and verification), identifies a clinical answer efficiently and effectively – genetic changes in the exome are expected to cause about 85% of known diseases. 

ExomeNext involves family centered analyses. Samples from all first-degree relatives of the proband (primary patient) are encouraged and accepted at the start of testing. Exome sequencing of an informative trio (proband, plus two first-degree relatives (typically the biological parents) is included in the price and turnaround time. Co-segregation analysis (family studies) is performed for all candidate alterations for the entire family, if all samples are received at the time of testing.

Coverage

In order for you to review the sequencing coverage of genes sequenced on ExomeNext, we have created an ExomeNext Interactive Gene Coverage Tool, a search engine that provides the average coverage for individual genes found on ExomeNext tests. Enter genes of interest to display the coverage for each consensus coding sequences (CDS) covered by ExomeNext’s platform. This provides you information about how well ExomeNext and/or ExomeNext-Select platforms cover any genes of interest for your patient before you order the test.

ExomeNext-Select

ExomeNext-Select is a customized exome sequencing option. It includes sequencing of the whole exome, but analysis is focused on a pre-selected list of genes based on your patient’s phenotypic presentation.  You can choose up to 500 genes for analysis through ExomeNext-Select.  Exome sequencing is performed on the proband and family members may be submitted for co-segregation analysis of candidate alterations.  Reporting of Secondary Findings is not included with this test option.  ExomeNext-Select can only be ordered directly through our online portal, AmbryPort 2.0.

EXOMENEXT KEY FACTS
Cost-effective Diagnostic rate higher than traditional approaches1,2
Trio testing guarantees highest detection rate Trio analysis (37%) vs. proband only (21%)3
Increased clinical sensitivity Comprehensive analysis and reporting of novel genetic etiologies (7-8% of results)3
Family-centered testing Co-segregation analysis always included for additional informative family members
Robust in-house gene database 23% of positive findings in recently characterized genes2
High diagnostic potential in complex phenotypes Dual diagnoses (7% of positive cases)3
Extensive medical review Unbiased, manual medical review not relying on phenotype-driven gene-lists
Inheritance-based model filtering Assumption-free analysis of all applicable inheritance patterns
Conservative bioinformatics filtering Increased probability to detect large indels and mutations in poorly covered regions

 

Disease Name 
Exome
Testing Benefits & Indication 
What are the benefits of testing?
  • End of the expensive, time-consuming and potentially invasive diagnostic odyssey
  • Cost-effective due to a high diagnostic rate, as compared to traditional approaches
  • Correction of potentially erroneous diagnosis/treatment
  • Allows for more accurate genetic counseling to be offered to patient/family
  • Complimentary re-analysis of the data to provide updated results (within 2 years of report being issued)

When is ExomeNext indicated?

  • The suspected genetic condition has become a “diagnostic odyssey,” with no genetic explanation identified from prior testing
  • Limited or no comprehensive tests are available for the suspected condition
  • Clinical presentation does not correspond with a known genetic disorder, but a novel genetic etiology is suspected
  • Clinical presentation is unclear/atypical and may involve multiple gene, making ExomeNext a more practical approach
  • Current treatment is not effective and an inherited cause is highly suspected
Test Description 

ExomeNext

ExomeNext includes sequencing of the exome using next generation sequencing methods targeted to the ~20,000 nuclear genes. Sequencing of the mitochondrial (mtDNA) genome is also performed. Sequencing of a trio of first-degree relatives occurs, which includes the patient of interest (proband) along with two first-degree relatives (usually the biological parents). Genetic alterations are filtered through our in-house bioinformatics pipeline and analyzed by our medical team.  Each alteration is reviewed to determine its pathogenicity and gene overlap with the patient’s clinical symptoms.  Candidate alterations are chosen for co-segregation analysis. The mitochondrial genome is also analyzed for characterized disease-causing mutations.  

Primary Report
Any genetic alteration that may be contributing to the patient’s described clinical phenotype is reported on the primary report. A clear, comprehensive report is issued for the proband and includes the overall result, summary of the identified gene, summary of nature of the alteration(s), co-segregation analysis results, overall coverage metrics, and a comprehensive list of all uncertain findings for candidate genetic etiologies.

Secondary Findings Report
Secondary Findings analysis and reporting is included with the ExomeNext, ExomeNext-Rapid, and ExomeNext-Prenatal test options. Secondary Findings include mutations in genes unrelated to the patient’s indication for testing. Secondary Findings will be reported in a separate report and will be issued after the Primary Report is completed. Secondary Findings reports are optional and available for the proband and family members chosen as part of the trio. Secondary Findings options can be found on the “ExomeNext Consent Form.”

ExomeNext-Select
 
ExomeNext-Select includes sequencing of the exome using next generation sequencing methods targeted to the nuclear genes. Sequencing of the patient of interest (proband) is included with this test option. Sequencing of the mitochondrial (mtDNA) genome is not performed. Family members, including first-degree relatives and other affected relatives, may be submitted along with the proband for co-segregation analysis.  Analysis is limited to a pre-selected phenotypic-driven list of up to 500 genes selected by the ordering provider at the time of testing. Genetic alterations are filtered through our in-house bioinformatics pipeline and analyzed by our scientific team. Each alteration is reviewed to determine its pathogenicity and gene overlap with the patient’s clinical symptoms. Secondary Findings analysis and reporting are not included with this option.

Mutation Detection Rate 

Ambry’s ExomeNext overall detection rate is 30% within characterized genes and an additional 8% for candidate genetic etiologies  (Farwell KD, et al.Genetics in Medicine, 2014). 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page. Special notes for ExomeNext samples:

Whole Blood
Requires 6-10cc blood (adult) and 5cc (pediatric minimum) per patient in purple top EDTA tube (preferred) or yellow top citric acetate tube.

Saliva
Saliva samples are only accepted for family member samples. Saliva samples are NOT accepted for the proband.

DNA
Requires 5μg at ~200ng/μl conc. of DNA .

Cultured Cells:
For exome sequencing, the following cultured cells are accepted:

  • Cultured fibroblasts
  • Cultured products of conception
  • Cultured amniocytes (9999P Only)
  • Cultured CVS (9999P Only)

 

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME
9999 ExomeNext 8-12 weeks
9999R ExomeNext-Rapid 8 days*
9999P     ExomeNext-Prenatal       3-4 weeks
9500 ExomeNext-Select 8-12 weeks

*Verbal result provided within 8 days, full report including mtDNA analysis, co-segregation analysis and Sanger confirmation provided within 14 days.

Tests 
References 
  1. Shashi V, et al. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med. 2014;16:176-182.
  2. Soden SE, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014 Dec 3;6(265):265.
  3. 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. 2014 Nov 6. [Epub ahead of print]
  4. Iglesias A, et al. The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. 2014;16:922-931.
  5. Biesecker LG and Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370:2418-25.
  6. Green RC, et al.; American College of Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74.
  7. ACMG Board of Directors. ACMG Policy Statement: Points to consider in the clinical application of genomic sequencing. Genet Med. 2012;14(8):759-76.
  8. Pussegoda KA. Exome sequencing: locating causative genes in rare disorders. Clin Genet. 2010 Jul;78(1):32-3.
  9. Choi M, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19096-101.
  10. Kalia SS, et al. American College of Genetics and Genomics. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2016 Nov 17. [Epub ahead of print].