Targeted variant testing

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 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 used in the following situations:

  • Diagnostic or predictive testing for 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 have an increased chance to 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 testing at GeneDx, select family members may be eligible for targeted variant testing at no additional charge through the Variant Testing Program (VTP)  
  • 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 relative

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

A classification of variant of uncertain significance (VUS) is assigned if there is insufficient information about the variant to lead to a benign, likely benign, pathogenic, or likely pathogenic interpretation. Because the clinical significance of a VUS is unknown, these test results generally cannot be used for risk assessment or medical management purposes.

In some situations, testing family members for the presence or absence of a VUS may provide information that could contribute to the eventual reclassification of a VUS to a clinically meaningful result. Family Members accepted into a GeneDx Variant Testing Program are offered targeted testing for the VUS at no additional charge, provided they submit all relevant clinical and/or family history information. GeneDx has sole discretion to make the final determinations for VTP participation. There is no guarantee that participation in a Variant Testing Program will lead to reclassification of a VUS. 

Cardiology Variant Testing Program (VTP)

Laboratories classify genetic changes as variants of uncertain significance (VUS) if there is insufficient 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 either a positive or negative result.

We consider requests for the Cardiology Variant Testing Program (VTP) for any individual found to have a VUS through testing at our laboratory. There is no charge for targeted variant testing for approved family members.

Which family members may be eligible for the VTP

  • Up to two affected family members may be approved to assess segregation.
  • If the family history is negative, both parents may be approved to assess de novo status.

Required documentation for consideration for the VTP

  • Clinical records of proband to confirm presentation is consistent with gene-disease association
  • Detailed family history or pedigree
  • Clinical records of family members applying for the VTP (see table below)
Gene/Disease Association Minimum Required Documentation
Cardiomyopathy Echocardiogram
Arrhythmia Relevant cardiac evaluation
Thoracic aortic aneurysm/dissection Echocardiogram including aortic root dimension
Heritable disorders of connective tissue Clinical documentation of gene-relevant features
Dyslipidemia Lipid panel
Hereditary hemorrhagic telangiectasia (HHT) Clinical documentation of Curacao criteria

Please submit the required documentation to our cardiology genetic counselors via fax 201-421-2010, email zebras@genedx.com, or call 301-519-2100 and ask to be speak to a cardiology genetic counselor. Please indicate you are submitting the information for cardiology VTP consideration and include the name and/or GeneDx accession number of the proband. Cases are typically reviewed within one week of receipt. After the request has been reviewed, a member of our VTP team will contact the ordering provider to discuss whether and which family members have been approved for the VTP or whether additional information is needed.

Reasons why a family might not be accepted into the Variant Testing Program:

  • The variant is in a gene that does not correspond to the documented presentation in the proband.
  • There are pathogenic or likely pathogenic variant(s) in the family that explain the disease.
  • There are no informative family members available for testing. (i.e. All affected relatives are deceased and/or unavailable, and no postmortem specimens are available.)
  • If both parents are not available in cases with a negative family history, we cannot accept only one parent as this does not aid in determining if a variant occurred de novo.

Reclassification of variants of uncertain significance requires substantial data and information from multiple sources. Therefore, there is no guarantee that participation in the Cardiology Variant Testing Program will lead to reclassification of a VUS.

For more information, please contact the cardiology genetic counselors at 301-519-2100.

Clinical Genomics (Exome and Genome Sequencing) Variant Testing Program (VTP)

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).

How do I determine if a variant is eligible for the Clinical Genomics 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-based 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.

Application process for the Clinical Genomics VTP

  • Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx Clinical Genomics genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with a Clinical Genomics genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • A member of our team will contact the ordering clinician after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing at no additional charge, we will discuss logistics of specimen submission at that time.

Reasons why a family might not be accepted into the Clinical Genomics VTP

  • The VUS is in a gene for which there is no currently described phenotype (i.e. candidate or novel gene).
  • There are no informative family members available for testing.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • Segregation studies involving genes with incomplete penetrance or variable age-of-onset are challenging, especially in unaffected individuals; therefore, VTP studies are less likely to be approved for such genes.
  • Segregation studies involving genes that may cause either an autosomal dominant or an autosomal recessive disorder are also more challenging than studies involving highly penetrant autosomal dominant genes; therefore, VTP studies are less likely to be approved for such genes.
  • Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Clinical Genomics genetic counselors at 301-519-2100.

GenomeDx (Microarray) Variant Testing Program (VTP)

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).

How do I determine if a variant is eligible for the GenomeDx VTP?
GeneDx considers requests for the GenomeDx Variant Testing Program for any individual found to have a VUS identified through whole genome microarray at our laboratory. In some circumstances we also offer the Variant Testing Program to parents of an individual with a likely pathogenic (LPATH) variant. There is no charge for variant testing for approved family members. GeneDx will make the final determinations for VTP in its sole discretion.

Application process for the GenomeDx VTP

  • In some cases, the ‘Recommendations’ section of the proband’s report may specify that testing for a VUS is available at no additional charge through the VTP for the biological mother and biological father of the proband. Clinical information on the parents (and proband) must be provided at the time of testing in order for targeted testing to be performed at no charge, but no additional prior approval is required for these cases.
  • If parents are not available, there may be other informative family members eligible for our VTP. Requests to consider testing for relatives other than the biological parents, or requests for other variants not specified in the ‘Recommendations’ section of the report, should be submitted for advance review.
  • Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx array genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with an array genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • A member of our team will contact the ordering clinician after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing, we will discuss logistics of specimen submission at that time.

Reasons why a family might not be accepted into the Clinical Genomics VTP

  • The VUS is in a genomic region that varies in copy number in the general population or for which there is no currently described phenotype.
  • There are no informative family members available for testing.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • Segregation studies involving genes with incomplete penetrance or variable age-of-onset are challenging, especially in unaffected individuals; therefore, VTP studies are less likely to be approved for such genes.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Array Genetic Counselors at 301-519-2100.

Hereditary Cancer Variant Testing Program (VTP)

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 either a positive or negative result.

We accept applications to the Hereditary Cancer Variant Testing Program for any individual found to have a VUS through hereditary cancer gene testing at our laboratory. There is no charge for variant testing for approved family members. GeneDx will make the final determinations for VTP in its sole discretion.

Application Process for the Hereditary Cancer VTP

  • Fax a detailed pedigree to our cancer genetic counselors at 201-421-2314 or send the information by email to zebras@genedx.com. Please place a note on the fax indicating that you are submitting the pedigree for VTP consideration.
  • Our VTP team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within 3 weeks of receipt.
  • A member of our VTP team will contact the ordering provider or genetic counselor after the case has been reviewed to let him/her know if any family members have been approved for acceptance into the VTP. If we are extending an offer for family member variant testing, we will discuss logistics of specimen submission at this time.

Note that testing through the VTP only includes testing for the familial VUS. More thorough cancer gene testing (as was performed in the original patient) is not provided through the VTP.

Some reasons why a family might not be accepted into the Hereditary Cancer VTP

  • The VUS is in a gene that does not correspond to the cancer history in the family.
  • The VUS is present in the mosaic state.
  • There are no informative living family members (i.e., all of the relatives with relevant cancer diagnoses are deceased).
  • In some cases, we may learn more, and the family may be better served, by clinical genetic testing in an affected family member rather than testing the submitted family member only for the VUS.
  • Variant studies of low or moderate penetrance cancer risk genes (like CHEK2 or BRIP1 for example) may be more challenging than studies of high penetrance genes (such as BRCA1 or BRCA2); for this reason, we may be less likely to approve variant studies for families with low to moderate risk gene variants.

Re-classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the Variant Testing Program will lead to reclassification of a VUS.

For more information please contact
The GeneDx Hereditary Cancer Genetic Counselors at 888-729-1206.

Metabolic/Mitochondrial Disorders Variant Testing Program (VTP)

Laboratories classify genetic changes as variants of uncertain significance (VUS) when 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 a 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).

How do I determine if a variant is eligible for the Metabolic/Mitochondrial Disorders VTP?
GeneDx considers requests for the Metabolic/Mitochondrial Disorders VTP for any individual found to have a VUS identified in a proband by metabolic or mitochondrial genetic testing 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.

Application process for the Metabolic/Mitochondrial Disorders VTP

  • Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx metabolic/mitochondrial genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with a genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • A member of our team will contact the ordering provider or genetic counselor after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing, we will discuss logistics of specimen submission at that time.

Note that testing through the VTP only includes testing for the familial variant(s) in question. More thorough testing that may have been performed on the original patient is not provided through the VTP.

Reasons why family members may not be accepted into the Metabolic/Mitochondrial Disorders VTP

  • There are no informative family members available for testing.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • The variant is in a gene that does not correspond well with the clinical phenotype reported in the proband or the medical history in the family.
  • Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.
  • Variant studies for the evaluation of a homozygous VUS identified in a gene associated with an autosomal recessive disorder are also often not informative and may be denied.
  • Segregation studies involving genes that may cause either an autosomal dominant or an autosomal recessive disorder are also more challenging than studies involving highly penetrant autosomal dominant genes; therefore, VTP studies are less likely to be approved for such genes.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Metabolic/Mitochondrial Genetic Counselors at 301-519-2100.

Neurology Variant Testing Program (VTP)

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).

How do I determine if a variant is eligible for the Neurology VTP?
GeneDx considers requests for the Neurology VTP for any individual found to have a VUS identified through Neurology genetic testing at our laboratory. Given the high rate of de novo variants in some neurological disorders, we may also offer the VTP to parents of an individual with a likely pathogenic (LPATH) variant. 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.

Application process for the Neurology VTP

  • In some cases, the ‘Recommendations’ section of the proband’s report may specify that testing for a VUS is available at no additional charge through the VTP for the biological mother and biological father of the proband. Clinical information on the parents (and proband) must be provided at the time of testing in order for targeted testing to be performed at no charge, but no additional prior approval is required for these cases.
  • If parents are not available, there may be other informative family members eligible for VTP testing. Requests to consider testing for relatives other than the biological parents, or requests for other variants not specified in the ‘Recommendations’ section of the report, should be submitted for advance review. Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx Neurology genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with a Neurology genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • A member of our team will contact the ordering provider or genetic counselor after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing at no additional charge, we will discuss logistics of specimen submission at that time.
  • Our typical policy is that we will test up to two informative family members at no charge. On a case by case basis, we may consider testing additional family members at no additional charge, depending on the disorder and the family history.

Reasons why a family might not be accepted into the Neurology VTP

  • There are no informative family members available for testing.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • The VUS is in a gene for which there is no currently described phenotype (i.e. candidate or novel gene).
  • The variant is in a gene that does not correspond well with the clinical phenotype reported in the proband or the medical history in the family.
  • Segregation studies involving genes with incomplete penetrance or variable age-of-onset are challenging, especially in unaffected individuals; therefore, VTP studies are less likely to be approved for such genes.
  • Segregation studies involving genes that may cause either an autosomal dominant or an autosomal recessive disorder are also more challenging than studies involving highly penetrant autosomal dominant genes; therefore, VTP studies are less likely to be approved for such genes.
  • Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Neurology Genetic Counselors at 301-591-2100.

Ophthalmology Variant Testing Program (VTP)

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).

How do I determine if a variant is eligible for the Ophthalmology VTP?
GeneDx considers requests for the Ophthalmology VTP for any individual found to have a VUS identified by a GeneDx Ophthalmology panel or single gene test. 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. Please note that GeneDx requires specific clinical documentation to ensure the most informative family members are tested. GeneDx will make the final determinations for VTP in its sole discretion.

GeneDx will test up to two affected family members at no charge through the Ophthalmology VTP. If the family history is completely negative, then testing of both parents is available at no additional charge to determine if the variant has occurred de novo.

Application process for the Ophthalmology VTP

  • Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx Ophthalmology genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with a genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • Please note that in order to qualify for the Ophthalmology VTP, we require detailed clinical records and may require documentation of specific studies, such as a comprehensive evaluation by an ophthalmologist or an electroretinogram (ERG), even on at-risk family members who are clinically asymptomatic. Because the clinical information is being used to assess segregation of a variant with disease in the family, detailed clinical records and the submission of a pedigree or family history information are required. 
  • A member of our team will contact the ordering provider or genetic counselor after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing at no additional charge, we will discuss logistics of specimen submission at that time.

Reasons why a family might not be accepted into the Ophthalmology VTP

  • There are no informative family members available for testing.
  • The variant is present with an allele frequency that is higher than expected for a pathogenic variant based on the prevalence of the disease in the population and on genetic heterogeneity, so familial segregation studies will not be informative.
  • The variant is in a gene that does not correspond to the disease phenotype in the family.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the Variant Testing Program will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Genetic Counselors at 301-591-2100.

Rare Disorders Variant Testing Program (VTP)

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).

How do I determine if a variant is eligible for the Rare Disorders VTP?
GeneDx considers requests for the Rare Disorders 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.

Application process for the Rare Disorders VTP

  • Please fax a detailed pedigree and any relevant clinical information/evaluations to the GeneDx Rare Disorders VTP genetic counselors at 301-519-2892, email zebras@genedx.com, or call 301-519-2100 and ask to speak with an Rare Disorders genetic counselor. 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 proband.
  • Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days, but please allow up to 3 weeks after receipt of the application for a reply.
  • A member of our team will contact the ordering clinician after the case has been reviewed to let him/her know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing at no additional charge, we will discuss logistics of specimen submission at that time.

Reasons why a family might not be accepted into the Rare Disorders VTP

  • The VUS is in a gene for which there is no currently described phenotype (i.e. candidate or novel gene).
  • There are no informative family members available for testing.
  • In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
  • Segregation studies involving genes with incomplete penetrance or variable age-of-onset are challenging, especially in unaffected individuals; therefore, VTP studies are less likely to be approved for such genes.
  • Segregation studies involving genes that may cause either an autosomal dominant or an autosomal recessive disorder are also more challenging than studies involving highly penetrant autosomal dominant genes; therefore, VTP studies are less likely to be approved for such genes.
  • Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.

Revising the classification of variants of uncertain significance takes a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.

For more information please contact
The GeneDx Rare Disorders genetic counselors at 301-591-2100.