Mitochondrial – Metabolic

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, 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 sample 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.