DISEASE INFORMATION
Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by mutations in the VHL tumor-suppressor gene.¹ VHL disease has a prevalence of approximately 1 in 50,000 and an incidence of 1 in 36,000 per year.² Affected patients have a predisposition for developing benign or malignant tumors or cysts in several organs of the body including hemangioblastomas in the central nervous system, renal cysts and renal cell carcinoma, pheochromocytomas, and endolymphatic sac tumors. The VHL gene encodes the VHL protein which is involved in multiple cellular processes including tumor suppression, oxygen-related gene expression, and protein assembly.³ Onset of disease occurs upon the loss of function of both VHL alleles. 

VHL disease can be classified into two types depending on the risk of developing pheochromocytomas. Type 1 individuals do not present with pheochromocytomas while Type 2 individuals do. Type 2 is further subdivided into Type 2A (patients with a low risk of developing renal cell carcinoma), Type 2B (patients with a high risk of developing renal cell carcinoma), and Type 2C (isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma).⁴ Genotypically, Type 2 patients have missense mutations, while deletions or nonsense mutations are usually found in Type 1 individuals.⁴ Currently, there is no cure for von Hippel-Lindau disease, but there are treatment options available which have proven helpful for disease management once the VHL disease type has been determined.⁵

TESTING BENEFITS & INDICATIONS

• Diagnostic testing for individuals known or suspected to have von Hippel-Lindau disease can assist in appropriate and effective treatment.
• Carrier screening for relatives of VHL disease patients can also be effective in determining if mutations are present in asymptomatic or pre-symptomatic individuals.
• Carrier testing for known familial mutations can further aide in determining at-risk individuals.
• Prenatal diagnosis may be considered in families with a previous history of VHL disease.
  

TEST DESCRIPTION
This Ambry Test is a gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-3 of the VHL gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Specific mutation analysis for individual VHL mutations known to be in the family is also available.

MUTATION DETECTION RATE
The Ambry Test: von Hippel-Lindau Disease (VHL) is designed and validated to be capable of detecting ~90% of described mutations in VHL. The clinical detection rate using the The Ambry Test: von Hippel-Lindau Disease (VHL)  is expected to be ~70%.⁶

SPECIMEN REQUIREMENTS
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 µg in TE at 50-100 ng/µl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

REFERENCES
¹Latif F et al. Science. 1993; 260(5112): 1317-20.
²Maher ER et al. J Med Genet. 1991; 28(7): 443-7.
³Gnarra JR et al. Nat Genet. 1994; 7(1): 85-90.
⁴Maher ER et al. J Med Genet. 1996; 33(4): 328-32.
⁵Lonser RR et al. Lancet. 2003; 361(9374): 2059-67.
⁶Stolle C et al. Hum Mut. 1998; 12: 417-423.

DISCLAIMER
This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing. The Ambry Test: von Hippel-Lindau Disease (VHL) analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, and small indels. It is not intended to analyze the following types of mutations: gross deletions/duplications, gross rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: von Hippel-Lindau Disease (VHL) is designed and validated to be capable of detecting ~90% of described mutations in VHL. von Hippel-Lindau disease is a complex clinical disorder, which in most cases (~70%) is due to alterations in VHL generally detected by the Ambry Test: von Hippel-Lindau Disease (VHL) except as noted above. Mutations in other genes or the regions not tested by the Ambry Test: von Hippel-Lindau Disease (VHL) can also give rise to clinical conditions similar to von Hippel-Lindau Disease. Although molecular tests are highly accurate, rare diagnostic errors may occur.  Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature.