DNA Testing

The VHL gene was mapped in 1993. Since then, DNA testing has moved from the experimental laboratories into the mainstream.

Anyone with a first- or second-degree relative with VHL is “at risk” for VHL. First-degree relatives are parents, children, sisters, and brothers. Second-degree relatives are cousins, aunts, uncles, grandparents, and grandchildren. The only way to confirm whether someone has VHL is through DNA testing. Most labs can do analysis from blood samples, some offer testing of saliva or cheek swab (buccal swab). The test must be processed at a clinical testing laboratory (lab) that has the necessary equipment and reagents to test for VHL.

You and your genetic counselor can find a lab to do the analysis at the Genetic Testing Registry (GTR) maintained at the US National Institutes of Health.

For blood testing: www.ncbi.nlm.nih.gov/gtr/tests/?term=vhl+blood

For testing from a saliva sample (spit tube): www.ncbi.nlm.nih.gov/gtr/tests/?term=vhl+saliva

For testing from a cheek swab (buccal swab): www.ncbi.nlm.nih.gov/gtr/tests/?term=vhl+buccal

A positive result is the identification of an alteration in the VHL gene—confirming that that person has VHL. If the DNA testing comes back negative, then both copies of the VHL gene are unaltered. In any medical test, there is always some margin for error. When the possibility of error is under 1–2%, it is considered to be as certain as possible in Nature. If the margin for error is 15%, you may wish to have additional testing. Most clinical testing today is highly accurate and reliable. “Analytical validity” rates are listed in the GTR.

Anyone at risk for VHL who has not received a negative DNA test should continue to follow a conscientious screening program to ensure early diagnosis of any VHL problems: www.vhl.org/screening-guidelines.

To initiate DNA testing in a given family, one family member with a clinical diagnosis of VHL should work with a geneticist or genetic counselor to submit a sample. The lab will perform a complete screen of the VHL gene to determine the specific alteration. Results of this test can take as much as 4–6 weeks. The complete screen will look for mutations in patients with a germline mutation in the VHL gene. Once a mutation has been identified, the exact change in this person’s VHL gene will be the same alteration that is passed within this family. In this way, testing of other family members without a clinical VHL diagnosis means that the lab can go directly to the previously identified alteration and check for that same mutation in this second person’s DNA. In other words, the first test in the family becomes a road map for the second test.

People who were tested prior to the year 2000 using a method called “linkage analysis” may wish to be re-tested using more modern methods of DNA sequencing. These improved techniques are significantly more reliable. There have been situations where the results of linkage analysis have proven not to be correct.*

A complete screening is needed for people who are the first in their family to be diagnosed with VHL, or for adoptees or others who do not have known blood relatives. For people in this situa­tion, it is important to choose a lab with a high “hit rate” or level of success in finding mutations.

The labs in the world that work most closely with the research teams, and know how to “go the extra mile” and find more difficult alterations are listed here. If a person seems clearly to have VHL based on the clinical criteria, but the alteration cannot be found in the VHL gene, they may wish to consult with one of these experts to check for methylation or other ways that the gene can be “silenced”and fail to function properly even though it is correctly spelt.

It is important to initiate DNA testing through a geneticist or genetic counselor to ensure a thorough discussion of the personal impact of the results. Ask your doctor or inquirer at a local medi­cal center if they have a department of “cancer genetics.” If so, this is the best place to assess your risk for VHL. If not, inquire in the Depart­ments of Obstetrics, Medicine, or Pediatrics. If they do not have an associated geneticist, they will know where to find one acceptable to your health plan.

If a mother-to-be with a family history of VHL or VHL-related tumors is having any genetic testing done, she may request that a VHL test be part of the scope of tests. Prenatal test results are usually part of the mother’s medical record, not the child’s. Ask to be sure.

A list of clinical testing labs with closest relationships to research groups is maintained here. Many commercial labs now offer DNA testing for VHL, and they generally do well. However, if this is the first person in a family to be tested, it is still a good idea to start with one of these expert labs. As of the date of publication of this booklet, the labs with the highest “hit rates” are those in Philadelphia, Pennsylvania; Padua, Italy; Ingelheim, Germany; and Lyon, France.

Catherine Stolle, Ph.D., FACMG
Molecular Genetics Laboratory
The Children’s Hospital of Philadelphia
Abramson Research Center 1106F
34th & Civic Center Boulevard
Philadelphia, PA 19104 USA
Phone: +1 215 590-8736
Fax: +1 215 590-2156
E-Mail: stolle@email.chop.edu

Dr. Christina Neuhaus
Bioscientia Institut für Laboruntersuchungen
Konrad Adenauer Str. 17
55218 Ingelheim GERMANY
Phone: +49 6132 781133
Fax: +49 6132 781262
E-Mail: Christine.Neuhaus@bioscientia.de

Dr. Sophie Giraud, Laboratoire de Génétique
Hôpital Edouard Herrior
69437 Lyon Cedex 3, FRANCE
Phone: +33 4 72 11 73 83
Fax: +33 4 72 11 73 81
E-mail: sophie.giraud@chu-lyon.fr

Dr. Alessandra Murgia
Rare Disease Center, Dept of Pediatrics
University of Padua
Via Giustiniani 3
Phone: +39 049 821-1430
Fax: +39 049 821-3502
E-mail: alessandra.murgia@unipd.it

*Pre-implantation Genetic Diagnosis (PGD) uses a modern type of linkage analysis customized to this one family which is highly accurate.

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