The mapping of the VHL gene to the tip of the short arm of chromosome 3 in 1988 was the first step towards developing a DNA test for VHL disease, and the isolation of the gene last year seemed to promise that DNA testing would become available for many families.¹ So how far have we progressed toward this aim?

By 1992 the position of the VHL gene had been pinpointed so accurately that it became possible to track a faulty gene through a family using DNA markers that were close to the gene. Although the gene tracking (or genetic linkage) approach could be as much as 99% accurate, there were a number of limitations. Firstly this technique can only be used when there are two family members known to be affected by VHL disease. It requires blood to be available from several key relatives. Even in families with a suitable structure for gene tracking, DNA markers may be uninformative for predictive testing.

However our experience of using gene tracking in Cambridge to determine the risk of 166 people with a family history of VHL disease was that in 86% of cases we were able to produce a low risk (1% carrier risk) or high risk result (99% carrier risk). So, in families with a suitable structure, DNA testing by gene tracking will usually be informative.

What about those families in which gene tracking is uninformative or not possible? The isolation of the VHL gene held out the hope of DNA testing by testing directly for the faulty gene (mutation) rather than gene tracking. Furthermore direct mutation analysis is more accurate than gene tracking. During the past year we and other research teams have been trying to determine in what proportion of families it would be possible to detect a mutation. Recent results suggest that the faulty gene can be identified in 70-75% of patients. A wide variety of mutations have been identified, but once a mutation is identified all family members can be screened.

It is well known that whereas phæochromocytoma² is rare in some VHL families, in others it is the most common complication of VHL. By comparing the types of mutations in families with and without phæochromocytoma we have found that some types of mutations are associated with a higher risk of phæochromocytoma than others. Thus when a large piece of the gene is missing (deletion) or the mutation is predicted to cause a shortened protein the incidence of phæochromocytoma is low. Missense mutations (when a single amino acid is changed) have a higher risk of phæochromocytoma and some missense mutations are particularly prone to cause phæochromocytoma. This work needs to be confirmed, but it suggests that in the future it may be possible to identify patients who are particularly likely to develop phæochromocytoma and so allow careful screening for this complication.

The work I have described is still at a research stage, but over the next two years DNA testing by direct mutation analysis will be introduced on a service basis for the 70-75% of patients in whom the faulty gene can be identified. The main advantage of DNA testing is that relatives shown not to be gene carriers can be reassured and spared repeated screening. However there are disadvantages and anyone wanting to undergo DNA testing should carefully consider the possible effects of a high risk result on insurance and employment prospects, etc., and emotional repercussions within the family of finding a child or relative is at high risk. Genetic testing of children is controversial, but in the case of VHL our policy has been to offer testing from age 5 years as after this the DNA result can be used to modify screening and so that test can benefit the child. Clearly even when DNA testing is possible it requires careful thought and should not be viewed as a simple blood test!

1. See the March and June 1993 issues of VHL Family Forum for background on genetic research, linkage analysis, and the finding of the VHL gene. Back issues available, see order form.

2. A tumor of the sympathetic nervous system, usually in the adrenal gland. See the VHL Handbook, and the December 1993 issue of the VHL Family Forum.

Editor's note: 1998 update: DNA testing has now moved from the research community to the clinical laboratories. DNA testing at the right center can now find more than 90% of the mutations in VHL families. Even if you have been previously told that they were unable to find the mutation, you can now try again. Click here for the current list of testing centers.

As published in the VHL Family Forum 2:3, September 1994. For permission to reprint, please contact the VHL Family Alliance at editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.