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Exome sequencing targets the protein-coding regions, called exons, of the approximately 20,000 genes in the genome. It is a powerful diagnostic tool, providing a definitive diagnosis in 20-50% of patients.^[3-4]

Exome sequencing can be used to identify the molecular basis of a genetic disorder in individuals:

• With a genetically heterogeneous disease as pathogenic findings could be present in many different genes
• With a long list of differential diagnoses
• With an atypical presentation of a genetic disorder
• Who have exhausted other currently available genetic testing options
• Who have suspected tissue-specific mosaicism

Genome sequencing targets both the protein-coding and non-coding regions of the human genome, allowing for the potential detection of characterized/pathogenic variants in regions that are not assessed by exome sequencing (ES). The non-coding regions include promoter, intronic, and untranslated regions. While much of the data generated from sequencing the genome is not well understood at this time, GS may provide more reliable coverage of the exonic regions^[5-6].

• Patient’s specimen. Please visit the Specimen Requirement Page for more information.
• Family member specimens, if appropriate depending on test requested.
• Completed test order signed by the qualified ordering healthcare provider and patient/guardian and, for trio/duo testing, relative consent(s).
• Medical records, including prior test results, consult notes, and pedigree/family history. Clients are encouraged to provide specific genes/disorders of interest and differential diagnosis.
   

Questions regarding pricing and billing can be directed to GeneDx Customer Service at support@genedx.com or by calling 1-888-729-1206.

The turnaround time will vary depending on the specific test requested. Please see the specific test page for additional information.

When a trio (patient plus both parents) is sent for XomeDx, XomeDxPlus, or GenomeSeqDx, sequencing is always performed on each member of the trio. This improves the sensitivity of the analysis when compared to testing only the patient. In some cases, including siblings or other relatives of the patient can be helpful. GeneDx will decide, in consultation with the ordering provider, which individuals will optimize our ability to identify a genetic cause of the patient’s features. We will also discuss the type of testing that is most useful and appropriate (i.e. exome sequencing or targeted variant testing to determine segregation). All individuals’ specimens should be submitted at the beginning of testing. Relative specimens may be collected and shipped separately from the patient specimen; however, relative specimens must be received within three weeks of receipt of the patient's specimen. In general, only a single report will be issued for in the patient's name only. However, the report will describe the inheritance and segregation of variants for all tested individuals.

Although sequence data may be generated on relatives, this data is only used to aid in the analysis of the patient's data. GeneDx does not conduct an independent analysis on relative specimens. A second, independent analysis on a relative can be ordered; additional fees apply.

Biological parents are typically the most informative specimens and are preferred whenever possible. If parents are unavailable, other relatives may be considered on a case-by-case basis. To review details of a specific case, you can contact a GeneDx Clinical Genomics Genetic Counselor at support@genedx.com or 1-888-729-1206

The diagnostic rate is highest when a trio is submitted/analyzed, as the inclusion of parental data improves the ability to classify variants. The absence of parental data may lead to the over reporting of variants of unknown significance that could otherwise be dismissed based on inheritance patterns.

Carrier testing for autosomal recessive conditions is best performed via other tests, such as ReproXpanded and/or GenPath: Inherigen.

Exome and genome sequencing will identify hundreds of thousands of variants. Variants are filtered using a variety of factors including population frequency, presence of gene and/or variant in HGMD or other databases, inheritance pattern, phenotype, severity of sequence change, and function in pathways. The clinical information provided by the ordering provider, including a description of the features, family history, and prior test results, is critical in the analysis of variants.

A single XomeDx or GenomeSeqDx report will be issued on the patient. A separate report will not be issued for family members who submitted a specimen for trio/duo testing. If additional reports are requested for other affected family members, additional fees may apply. The report issued for the patient will contain variants in genes previously implicated in a human disease similar to that affecting the patient or in genes hypothesized to be related to the cause of the disease (candidate genes), based upon the function, tissue of expression, and phenotype of model organisms with alterations in the gene. Variants in candidate genes may also be reported based on internal data, such as observations of previous XomeDx cases with similar phenotypes and types of variations in the same gene.

The American College of Medical Genetics and Genomics (ACMG) recommends that pathogenic and likely pathogenic variants identified in a specific subset of genes associated with medically actionable, inherited disorders be reported for all patients undergoing exome or genome sequencing.

Please refer to the latest version of the ACMG recommendations for reporting of secondary findings in clinical exome and genome sequencing for complete details of the genes and associated genetic disorders. Secondary findings will be included in all exome and genome sequencing reports, unless a patient opts-out of receiving this information in the Patient Consent section of the test requisition form. The presence of any secondary finding(s) reported for the patient will be provided for all relatives included as part of the patient's test. GeneDx does not conduct an independent evaluation of secondary findings in relatives. Relatives have the ability to opt-out of receiving secondary findings. Secondary findings will be confirmed by an alternate test method when needed.

Yes, as a separate test. An independent analysis for ACMG secondary findings can be ordered via XomeDxSlice, test code 706. ACMG secondary findings are also reported as part of XomeDx®Insights, an exome based test designed for generally healthy adults who would like to learn about medically relevant changes in their genetic code, and their risk to have or develop certain genetic conditions.

 A single report will be issued for the patient (affected individual). No separate reports will be issued for the parents or other unaffected relatives. Variants known to be benign (not associated with any disease) and/or commonly seen in many other healthy people will not be reported. If a patient opts-out of receiving secondary findings, we will not analyze or report variants in the ACMG-recommended genes unless they are related to the patient’s phenotype.

Given the large number of genes analyzed via exome or genome sequencing, pathogenic variants may be detected in genes that may be medically significant, but not associated with the primary reason for testing in a given patient.

In rare cases, GeneDx may report an incidental finding in a gene that is not one of the genes recommended by the ACMG. These reported findings must be pathogenic variants identified in the coding exons of genes, considered medically actionable, with the results expected to have a significant impact on the patient's health. These findings are not reported without prior discussion with the ordering clinician.

It is possible that entire genes may not be captured and sequenced in a particular patient, though in general we expect that there are only small portions of different genes not amenable to evaluation. Some exons have low or no coverage because probes have not been designed or are unavailable for these regions. It may be challenging to obtain usable sequence data for some regions. To check coverage of specific genes via exome or genome sequencing, visit the XomeDx®Slice Tool.

Approximately 98% of the targeted region of an affected individual's exome will be assessed with the XomeDx tests at a minimum of 10x coverage, the minimum read depth necessary to detect a variant. Across the exome, the average depth of coverage is 100-120x. The test report will include case-specific exome coverage. Average read depth statistics for XomeDx tests are as follows:

Since 2014, GeneDx has been detecting copy number variants (CNVs) directly from exome sequencing data using an in-house developed algorithm^[7]. This method can reliably detect most deletions and duplications involving three or more coding exons; smaller deletions or duplications may not be reliably identified. All reported CNVs are confirmed by an orthogonal method such as array CGH, MLPA, or PCR and parental confirmations for reportable CNVs are reported without additional charges. CNV analysis may not be possible in approximately 5% of specimens. All Xome-based reports will include whether CNV detection was possible. At this time, exome based technology is not a replacement for the sensitivity of exon level aCGH.

Our CNV analysis via XomeDx can identify:

• Large multi-gene chromosomal aberrations
• Small, partial gene, and intragenic CNVs; deletions and duplications of three exons or larger are reliably identified
• CNVs of one to two exons in size may be identified and comprise >50% of our previously reported exon-level variants
• Chromosomal aneuploidy
• Uniparental disomy (UPD), including isodisomy and heterodisomy
• Inheritance of CNVs when a trio is submitted

CNV analysis is limited or may not be possible in regions with reduced coverage, extreme GC- or AT-content, or significant homology to pseudogenes or segmental duplications. Our method may not always detect balanced aberrations, mosaicism, deletions/duplications involving only part of an exon, or CNVs in non-coding regions of the genome.

A negative report means we did not detect any variants related to the reported clinical features in any area of the exome or genome that was tested at the time of the analysis. It certainly is possible that the cause of the affected individual’s disease is due to an underlying genetic condition. There could be a variant in a region of the exome or genome that is not covered by this test, a type of variant that cannot be detected, or there may be a variant that is observed in a gene not yet known to cause human disease. Depending on the specific situation and condition of interest in a given family, additional genetic testing may be warranted.

Reanalysis of the previously generated sequencing data can be considered, since technology and bioinformatics pipelines continuously improve and new disease genes are published.
 

Reanalysis is the process of reexamining the sequencing data generated from the XomeDx or GenomeSeqDx tests. This is most commonly requested when the initial sequencing did not yield a definitive result and may be especially helpful in cases where there are changes to the phenotype. Generally, reanalysis is recommended to occur at least two years after the date of the initial XomeDx or GenomeSeqDx report. Currently, we offer a one-time, no-charge reanalysis for every XomeDx, XomeDxPlus, GenomeSeqDx test.

Family members can be tested for variants identified in the initial patient. If the variants detected in the patient are classified as pathogenic or likely pathogenic, family member testing can be ordered via Targeted Variant Testing (Site-Specific).

Laboratories classify genetic changes as variants of uncertain significance (VUS) if there is incomplete or conflicting information about the health consequences of the variant. In some cases, testing family members for the presence or absence of the VUS may contribute to a better understanding of the variant and may be one piece of evidence leading to eventual reclassification of a VUS as a pathogenic, likely pathogenic, benign, or likely benign variant. For such cases, GeneDx has established a Variant Testing Program (VTP). GeneDx considers requests for the Clinical Genomics VTP for any individual found to have a VUS in a disease-causing gene through exome or genome sequencing at our laboratory. These studies will be performed at no additional charge for select and pre-approved family members who meet certain criteria and for whom appropriate clinical information is provided. Genetic testing for other variants or additional family members, including predictive testing, is not included in our VTP and can be ordered separately for charge. GeneDx will make the final determinations for VTP in its sole discretion.

Inquiries regarding the Clinical Genomics VTP can be directed to GeneDx Clinical Genomics genetic counselors via email support@genedx.com, phone 1-888-729-1206, or fax 301-519-2892, and should include a detailed pedigree and any relevant clinical information/evaluations. Please be sure to indicate that you are submitting the information for VTP consideration, and include the name and/or GeneDx accession number of the original patient.

You can contact a Clinical Genomics Genetic Counselor through our Customer Service team:

Email: support@genedx.com

Yes, GeneDx offers needs-based programs for patients through two different networks: the iHope Whole Genome Sequencing Program and the Odyssey Exome Sequencing Program