GeneDx Targeted Variant Testing

When genetic testing identifies variant(s) in a patient, targeted variant testing may be indicated for family members. Targeted variant testing is less costly than diagnostic analysis of the whole gene or panel of genes. Additionally, in most cases targeted variant testing for pathogenic or likely pathogenic variant(s) will provide a straightforward “negative” or “positive” result.

GeneDx offers a comprehensive menu of targeted variant testing options to meet the needs of families and healthcare providers. These tests are available for families who had previous testing at GeneDx as well as for families who had prior testing at another laboratory. Targeted variant testing is often ordered by healthcare providers in the following situations:

Diagnostic or predictive testing for a patient’s at-risk family members after pathogenic or likely pathogenic variant(s) are identified by genetic testing of an affected patient
Carrier testing to assess reproductive risk for people who may be a carrier of a familial genetic disorder
Segregation analysis to help clarify the clinical significance of a variant of uncertain significance (VUS). If the VUS was identified through genetic testing at GeneDx, eligible family members may receive targeted variant testing at no additional charge.
CLIA-approved laboratory confirmation of variant(s) previously identified in a research setting
Mosaicism testing for a specific variant previously identified in a different tissue in an affected patient or in a family member

See the test options below for more information about the specific services that we provide.

Carrier/variant specific testing

FAMILIAL RISK ASSESSMENT
Once a pathogenic or likely pathogenic variant is identified in the proband, targeted testing of family members may be indicated to evaluate their risk.

Targeted testing is less costly and more rapid than diagnostic analysis of the whole gene or panel of genes and will provide either a “negative” or “positive” result
GeneDx offers targeted testing for families whether they have had previous testing at GeneDx or another laboratory
Targeted testing for the familial variant(s) is available in any gene for both symptomatic and asymptomatic individuals, and for autosomal dominant and recessive, X-linked or maternally inherited mitochondrial variants
The ordering provider will need to provide information on the proband’s previous testing results, including the gene(s) and variant(s), when ordering (see links to the left for details)
To order targeted testing for family members:
- Print out a GeneDx test requisition form or click here for online ordering
- Select the desired test from the ‘Targeted Variant Testing’ section
- Provide information on the proband’s previous testing results, including the gene(s) and variant(s) that need to be tested

Click here for more information

VARIANT OF UNCERTAIN SIGNIFICANCE (VUS) SEGREGATION ANALYSIS
When a variant of uncertain significance (VUS) is identified in the proband, testing family members may provide more information about the potential pathogenicity of the variant.

GeneDx offers targeted testing for families whether they have had previous testing at GeneDx or another laboratory
Targeted testing for a VUS is available in any gene for both symptomatic and asymptomatic individuals, and for autosomal dominant and recessive, X-linked or maternally inherited mitochondrial variants
The ordering provider will need to provide information on the proband’s previous testing results, including the gene(s) and variant(s), when ordering (see links to the left for details)
To order targeted testing for family members:
- Print out a GeneDx test requisition form or click here for online ordering
- Select the desired test from the ‘Targeted Variant Testing’ section
- Provide information on the proband’s previous testing results, including the gene(s) and variant(s) that need to be tested
If the VUS was identified through testing at GeneDx, family members may be eligible for targeted testing at no additional charge through the Variant Testing Program. Click here for more information.

Family member previously tested at GeneDx

What information do I need to provide to order targeted variant testing on an individual when their family member was tested at GeneDx?

If available, please submit the GeneDx laboratory report on the family member
Please list the variant and provide the family member’s specimen ID/name/date of birth
- For Nuclear Gene Variants:
  - The name of the gene
  - The variant in cDNA-level notation (e.g. residue c.123 G to T, where c.1 is the A of the initiator ATG)
- One of the following:
  - The variant given in protein-level notation (e.g. Gly12Ser or G12S)
  - The variant given in gDNA-level notation, with reference to a specific public reference sequence
  - A DNA sequence at least 30 bases long with the altered base and variant indicated
- For Mitochondrial (mtDNA) Variants:
  - The name of the gene
  - The position in the mitogenome (m.) using reference sequence NC_012920

How do I order targeted variant testing on an individual when their family member was tested at GeneDx?

Use a GeneDx Test Requisition Form or order online
Select Targeted Variant Testing (Inherited Cancer Requisition) or Targeted Variant Testing and Special Services (all other requisitions)
Provide the name of the gene and name of the variant (using the format above)
Provide the family member’s specimen ID Number/name/date of birth
Enclose a copy of the GeneDx report on the family member, if available
For mitochondrial DNA (mtDNA) variants, select one of the Known mtDNA Variant(s) test options
Please refer to our specimen requirements page prior to submitting a specimen

What is the turn-around time?

Test results are generally available in 2-3 weeks*
Written report(s) are sent to the ordering healthcare provider

*Reporting times are typical estimates, but could be extended in situations outside GeneDx’s reasonable control

Family member previously tested by another, non-GeneDx laboratory

GeneDx can provide targeted variant testing to family members when testing was originally performed by another, non-GeneDx laboratory. We recommend submitting a specimen from a relative with the variant(s) of interest as a positive control, but this is not required.

What information do I need to provide to order targeted variant testing on an individual when their family member was tested at another diagnostic laboratory?

If available, please submit the outside molecular diagnostics laboratory report on the family member
Please identify the variant:

- For Nuclear Gene Variants:
  - The name of the gene
  - The variant in cDNA-level notation (e.g. residue c.123 G to T, where c.1 is the A of the initiator ATG)
  - One of the following:
    - The variant given in protein-level notation (e.g. Gly12Ser or G12S)
    - The variant given in gDNA-level notation, with reference to a specific public reference sequence
    - A DNA sequence at least 30 bases long with the altered base and variant indicated
- For Mitochondrial (mtDNA) Variants:
  - The name of the gene
  - The position in the mitogenome (m.) using reference sequence NC_012920
- For Copy Number Variants (CNVs):
  - Email support@genedx.com to confirm availability and gene coverage (if needed)
- For single gene or intragenic CNVs:
  - The name of the gen
  - The exons involved and transcript number OR genome build and genomic coordinates
- For multigenic CNVs:
  - The genome build and genomic coordinates
  - For GeneDx portal orders, select a gene from within the genomic region from the list. If you do not know or cannot find any genes within the region, select “XYZ” from the list as a placeholder

How do I order targeted variant testing on an individual when their family member was tested at another diagnostic laboratory?

Use a GeneDx Test Requisition Form or order online
Select Targeted Variant Testing (Inherited Cancer Requisition) or Targeted Variant Testing and Special Services (all other requisitions)
Provide the name of the gene and name of the variant (using the format above)
Enclose a copy of the outside diagnostics laboratory report, if available
For mitochondrial DNA (mtDNA) variants, select one of the Known mtDNA Variant(s) test options
Please refer to our Specimen Requirements page prior to submitting a specimen

Is a positive control required?

No, a positive control is not required but it is highly recommended*
Without a positive control, we may not be able to confirm that a negative result is truly negative
Please label the test requisition form for the positive control individual with “Positive Control Only – No Report”
If requested, a report for the positive control family member is available for an additional fee
Please call one of our genetic counselors if you would like to discuss the submission of a positive control

*A positive control is not needed for mtDNA variants

What is the turn-around time?

Results are generally available in 2-3 weeks*
Written report(s) are sent to the ordering healthcare provider

*Reporting times are typical, but could be extended in situations outside GeneDx’s reasonable control

Previously tested at a research laboratory

We can analyze almost any gene to confirm a variant that has been identified in a research laboratory. Unlike most research laboratories, GeneDx is a CLIA-certified clinical service laboratory and can release results of testing to referring healthcare provider for use in diagnosis, counseling, and development of a treatment plan.

Guidelines:

Must be ordered by a healthcare provider
A new specimen (usually blood or buccal swab) from the individual is required to confirm that the variant is present
This confirmation of the variant in the previously-tested individual is necessary before we can perform targeted variant testing or prenatal diagnosis in the family

What information do I need to provide to order a variant confirmation test?
Please provide variant information to GeneDx prior to sending in the specimen(s). This information may be in the form of a publication, lab report, or other communication from the laboratory, in which the variant was previously observed

To clearly identify the variant, please provide:

For Nuclear Gene Variants

The name of the gene
The variant in cDNA-level notation (e.g. residue c.123 G to T, where c.1 is the A of the initiator ATG)
One of the following:
- The mutation variant given in protein-level notation (e.g. Gly12Ser or G12S)
- The mutation variant given in gDNA-level notation, with reference to a specific public reference sequence
- A DNA sequence at least 30 bases long with the mutated altered base and mutation variant indicated

For Mitochondrial (mtDNA) Variants:

The name of the gene
The position in the mitogenome (m.) using reference sequence NC_012920

How do I order Variant Confirmation?

Use a GeneDx Test Requisition Form. This test can be found in the Targeted Variant Testing section located after the main test list on all requisition forms
OR Order Online by selecting the appropriate targeted test and indicate “Research confirmation” in the comments section
Provide the name of the gene and name of the variant (using the format above)
Enclose a copy of the research report, if available
For mitochondrial DNA (mtDNA) variants, select one of the Known mtDNA Variant(s) test options
Please refer to our Specimen Requirements Page prior to submitting a specimen

What is the turn-around time?

Test results are generally available in 3-4 weeks*
Written report(s) are sent to the ordering healthcare provider

* Reporting times are estimates, but could be extended in situations outside GeneDx’s control

Targeted mosaic variant testing

TARGETED MOSAIC VARIANT TESTING: TARGETED TESTING TO EVALUATE FOR MOSAICISM FOR A KNOWN FAMILIAL VARIANT

GeneDx offers targeted testing to evaluate for mosaicism for a familial variant previously identified in an individual or in a family member. Targeted Mosaic Variant Testing could be considered in the following scenarios:

Testing parent(s) to clarify future reproductive risks when a variant was identified in a child
Testing a parent who is suspected to be mosaic due to a mild clinical presentation or the presence of only certain tissue-specific features of the disorder
Testing additional tissue specimens to evaluate for the possibility of tissue-specific mosaicism in a proband
CLIA confirmation of suspected mosaic findings identified by a research study

Targeted Mosaic Variant Testing is available for many variants in genes on the GeneDx testing menu. In many cases, Targeted Mosaic Variant Testing is also available for individuals who had variants identified by testing at an outside laboratory or as part of a research study. If the family has not had prior testing at GeneDx, please see the table below for the specific requirements. At this time, Targeted Mosaic Variant Testing is not available for copy number variants (CNVs). Additionally, there are some genes or portions of genes that are not amenable to Targeted Mosaic Variant Testing for sequencing variants. If prior trio testing was performed including the patient and both parents as part of exome or genome sequencing, an Xpanded panel, or another testing scenario, please contact GeneDx in advance of specimen submission to discuss the utility of Targeted Mosaic Variant Testing.

Scenarios when mosaic carrier analysis could be considered:	Specimen from Patient as Positive Control	Copy of Report from Non-GeneDx Laboratory	Preferred Specimen Type
1. Evaluate for parental mosaicism when proband not tested or tested by Sanger sequencing: Parents not tested or tested by Sanger sequencing.	Not Necessary	Not Necessary	Blood or Buccal swab
2. Evaluate for parental mosaicism when proband tested by research study or at outside lab: Parents not tested or tested by Sanger Sequencing	Required	Required	Blood or Buccal Swab
3. Evaluate for mosaicism in an affected parent: Parent had prior testing as part of trio testing for proband that was negative for the variant.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Please call in advance to discuss.
4. Evaluate for parental mosaicism when there are multiple affected children: Parent had prior testing as part of trio testing for proband that was negative for the variant.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Please call in advance to discuss.
5. Evaluate for suspected mosaicism in proband previously reported to be heterozygous for variant: Proband reported to be heterozygous for variant by prior testing, but clinical features suggest possible mosaicism.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Please call in advance to discuss.
6. Evaluate proband to differentiate acquired or somatic mosaicism from constitutional variant: Proband is heterozygous or mosaic for variant in DNA extracted from blood.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Not necessary if prior testing done at GeneDx. Required if done at an outside laboratory.	Skin punch biopsy is recommended

To order Targeted Mosaic Variant Testing, please use this requisition form, and provide the requested information:

The name of the gene
The specific variant for mosaic targeted testing
If the patient or a family member was previously tested at GeneDx, provide the GeneDx accession number and/or the full name of the relative

Please see our standard Specimen Requirements Page for obtaining and shipping specimens. The requisition form MUST accompany the specimen or testing may be cancelled or delayed.

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