Using a combination of quantitative Southern blot analysis and DNA sequence analysis, germline mutations in the VHL gene have been identified in about 250 consecutive patients with well-documented (pathology-proven) VHL disease seen at the National Cancer Institute (NCI) since 1995, with no false negatives and no false positives. The sensitivity and specificity of the assays used to detect VHL gene mutations, therefore, are very high.
If a disease-causing mutation is identified in an affected or an at-risk individual, that individual will be predisposed to developing tumors characteristic of VHLD. Periodic screening of target organ systems is recommended for early detection and treatment of tumors. Molecular testing of offspring should be suggested, as they are at 50% risk of inheriting the disease-causing mutation. The parents of the proband should be offered molecular testing, as they may have unappreciated disease. The risk to siblings depends on the mutation status of the parents.
The interpretation of a negative mutation screen depends on the circumstances surrounding the testing and the strength of the clinical diagnosis in the affected family member. A negative test in an individual at risk for a known VHL gene mutation is definitive. The individual is not at risk for developing VHLD and need not undergo clinical screening for VHLD-associated tumors.
In screening of an unaffected at-risk individual for an unknown mutation in the VHL gene, however, a negative mutation screen indicates only that the individual does not have a germline VHL gene mutation. This may be because (1) the individual did not inherit the mutant allele from the affected relative (i.e., a parent), (2) the affected relative does not have VHLD (i.e., as a result of an incorrect or inconclusive diagnosis), or (3) if the individual is the parent, he or she may be mosaic for a mutation detectable in affected offspring. Whenever possible, careful clinical evaluation or molecular analysis of an affected family member is suggested to improve the accuracy of the test interpretation.
For an individual with a clinical diagnosis of VHLD but no family history, a negative mutation screen indicates that either the patient is a phenocopy (coincidental occurrence of tumors typical of VHLD but without a gene mutation) or a mosaic (with a mutation in some, but not all, cells of the body). Mosaicism has been documented in the affected but mutation-negative parents of patients with a germline VHL gene mutation.2 The frequency of mosaicism is not known but is believed to be low (i.e., <5%). If the diagnosis of VHLD is supported by pathologic findings (i.e., magnetic resonance imaging [MRI] of brain or spine, eye examination, abdominal ultrasound or computed tomography [CT] scan, urinary catecholamines, etc.), then the patient is more likely to be mosaic and should be periodically screened for additional tumors characteristic of VHLD. Offspring (if any) should be considered at risk and may wish to undergo periodic clinical screening for tumors or molecular analysis. The degree of risk (0-50%) depends on the extent of mosaicism and the potential for transmitting the mutant allele, neither of which can be determined.
For patients who do not fulfill the clinical criteria for VHLD diagnosis because they have a single type of tumor and no family history, a negative mutation screen would indicate that they are very unlikely to have VHLD. The possibility of mosaicism cannot be entirely ruled out, however. Although routine clinical surveillance for characteristic VHL tumors would not appear warranted, regular follow-up visits to a physician regarding the initial tumor would be expected. Likewise,routine screening of offspring would not be indicated unless the proband develops additional tumors (especially of another typical organ system) or if the offspring begins to develop symptoms of VHLD.
Occasionally, a base change in the VHL gene will be detected that is neither a known disease-causing mutation nor a polymorphism. These base changes of "unknown significance" with regard to VHLD are generally missense mutations or mutations in introns outside the consensus splice sequences. Novel mutations may be evaluated as disease-causing mutations or polymorphisms by criteria described by Cotton and Scriver.10 In such cases, it is helpful to test other affected or unaffected family members, or both, to determine whether the mutation segregates with the disease.
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