Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome (VHL) is a hereditary cancer predisposition syndrome with a reported prevalence between 1:36,000 and 1:85,000. VHL is characterized by an increased risk for central nervous system hemangioblastomas (60–80%), retinal capillary hemangiomas (50–60%), renal cysts and carcinomas (30–60%), pancreatic cysts (30–65%), pheochromocytomas (11–19%), epididymal cystadenomas (26%), and endolymphatic sac tumors (2–10%).1 Clinically, VHL families can be subdivided on the basis of absence (Type 1) or presence (Type 2) of pheochromocytoma (PCC). Patients with VHL type 1 are at high risk for hemangioblastoma (HB) and renal cell carcinoma (RCC) and low risk for PCC. Patients with VHL type 2A have an increased risk for HB and PCC, but low risk for RCC. VHL type 2B are at high risk for HB, RCC and PCC while type 2C are at low risk for HB and RCC and high risk for PCC. VHL is highly penetrant and all individuals who harbor a mutation in the VHL gene will develop symptoms by 65 years of age. However, the clinical manifestations and disease severity are highly variable, even among family members with the same mutation.

Tests Available

Forms and Documents

Test Details

  • An individual with a personal history and family history of tumors or other clinical features associated with Von Hippel-Lindau (VHL), such as Hemangioblastomas of the spine, brain or retina; renal and/or pancreatic cysts; renal cell carcinoma; pheochromocytomas; pancreatic neuroendocrine tumors; epididymal cystadenomas; endolymphatic sac tumors.
  • An individual with early-onset renal cell carcinoma OR renal cancer at any age and a personal or family history of any other features associated with VHL
  • An individual with multiple hemangioblastomas of spine, brain, or retina OR a single hemangioblastoma and a personal or family history of other features associated with VHL
  • An individual with a pheochromocytoma, especially if young and/or bilateral.
  • An individual with a multiple renal and pancreatic cysts and a family history of other features associated with VHL
  • An unaffected individual with a family history suggestive of VHL (see above) when an affected individual is unavailable for his or her own genetic testing

Ordering

332
3 weeks
2-5 mL Blood - Lavender Top Tube
Buccal Swabs | Fibroblasts (separate charge for cell culture may apply)

Billing

81403x1, 81404x1
No
Yes
* For price inquiries please email zebras@genedx.com

References

  1. The Human Gene Mutation Database (HGMD), Institute of Medical Genetics in Cardiff, 2008. www.hgmd.cf.uk/ac/index.php
  2. Wong WT et al. Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis. Arch Ophthalmol 2007;125(2):239-45
  3. Shehata BM et al., Von Hippel-Lindau (VHL) disease: an update on the clinico-pathologic and genetic aspects. Adv Anat Pathol 2008;15(3):165-71
  4. Couch V et al. von Hippel-Lindau Disease. Review. Mayo Clin Proc 75:265-272, 2000
  5. Hoebeeck J et al. Rapid detection of VHL exon deletions using real-time quantitative PCR. Lab Invest 2005;85(1):24-33
  6. Stolle C et al., Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12(6):417-23
  7. Bento M et al., Congenital polycythemia with homozygous and heterozygous mutations of von Hippel-Lindau gene: five new Caucasian patients. Haematologica 90:128-129, 2005
  8. Mannelli M et al. Genetics and biology of pheochromocytoma. Exp Clin Endocrinol Diabetes 2007;115(3):160-5
  9. Kaelin WG, Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2(9):673-82
  10. Liu E et al., The worldwide distribution of the VHL 598C>T mutation indicates a single founding event. Blood 2004;103(5):1937-40
  11. Pastore Y et al., Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital Polycythemia. Am J Hum Genet 73:412-419, 2003
  12. Cario H et al., Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 90(1): 19-24, 2005
  13. Maher ER et al., Phenotypic expression in von Hippel-Lindau Disease. J Med Genet 33:328-332, 1996

Forms and Documents

Test Details

AHI1, ALG8, ALG9, ANKS6, BICC1, CC2D2A, CEP120, CEP290, CEP83, COL4A1, CRB2, CSPP1, GANAB, GLIS2, GLIS3, HNF1B, IFT172, INVS, IQCB1, JAG1, LRP5, MKKS, MKS1, NEK8, NOTCH2, NPHP1, NPHP3, OFD1, PAX2, PKD1, PKD2, PKHD1, PMM2, PRKCSH, RMND1, RPGRIP1L, SEC61A1, SEC63, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, TSC1, TSC2, TTC21B, UMOD, VHL, WDR35
  • Molecular confirmation of a clinical diagnosis;
  • Development of appropriate evaluation and management plan;
  • Evaluation of family members as possible donors for kidney/liver transplantation;
  • Testing of at-risk relatives for specific known variant(s) previously identified in an affected family member;
  • Prenatal diagnosis for known familial pathogenic variant(s) in at-risk pregnancies;
  • Genetic counseling, especially recurrence risk and prenatal diagnosis

Sequencing of the PKD1 gene is challenging due to high homology with six known pseudogenes (exons 1-33).
Our NGS assay is specifically designed to provide superior mapping quality and uniform coverage across the coding region of PKD1, enabling robust detection of variants including indels. For mapping quality of >20, 99.7% of the targeted nucleotides have a mean coverage of 264 reads; even at a mapping quality of >40, mean coverage is 254x.
PKD1 variants are confirmed by long-range, nested PCR and capillary sequencing.
For Deletion/Duplication analysis, Multiplex Ligaton-Dependent Probe Amplification (MLPA) is performed.

Ordering

TG23
4-6 weeks
2-5 mL Blood - Lavender Top Tube
Buccal Swabs | Extracted DNA

Billing

81406x2; 81407x1; 81408x2
No
Yes
* For price inquiries please email zebras@genedx.com

Forms and Documents

Test Details

AHI1, ALG8, ALG9, ANKS6, BICC1, CC2D2A, CEP120, CEP290, CEP83, COL4A1, CRB2, CSPP1, GLIS2, GLIS3, IFT172, INVS, IQCB1, JAG1, LRP5, MKKS, MKS1, NEK8, NOTCH2, NPHP1, NPHP3, OFD1, PAX2, PMM2, RMND1, RPGRIP1L, SEC61A1, SEC63, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, TSC1, TSC2, TTC21B, UMOD, VHL, WDR35
  • Molecular confirmation of a clinical diagnosis;
  • Development of appropriate evaluation and management plan;
  • Evaluation of family members as possible donors for kidney transplantation;
  • Testing of at-risk relatives for specific known variant(s) previously identified in an affected family member;
  • Prenatal diagnosis for known familial pathogenic variant(s) in at-risk pregnancies;
  • Genetic counseling, especially recurrence risk and prenatal diagnosis

Ordering

TG25
4 weeks
2-5 mL Blood - Lavender Top Tube
Buccal Swabs | Extracted DNA

Billing

81405x1; 81406x2; 81408x1
No
Yes
* For price inquiries please email zebras@genedx.com

Forms and Documents

Test Details

AHI1, ALG9, ANKS6, BICC1, CC2D2A, CEP120, CEP290, CEP83, COL4A1, CRB2, CSPP1, GLIS2, GLIS3, HNF1B, IFT172, INVS, IQCB1, JAG1, MKKS, MKS1, NEK8, NOTCH2, NPHP1, NPHP3, OFD1, PAX2, PMM2, RMND1, RPGRIP1L, SEC61A1, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, TSC1, TSC2, TTC21B, UMOD, VHL, WDR35
  • Molecular confirmation of a clinical diagnosis;
  • Development of appropriate evaluation and management plan;
  • Evaluation of family members as possible donors for kidney/liver transplantation;
  • Testing of at-risk relatives for specific known variant(s) previously identified in an affected family member;
  • Prenatal diagnosis for known familial pathogenic variant(s) in at-risk pregnancies;
  • Genetic counseling, especially recurrence risk and prenatal diagnosis

Ordering

TG24
4 weeks
2-5 mL Blood - Lavender Top Tube
Buccal Swabs | Extracted DNA

Billing

81405x2; 81406x1; 81408x1
No
Yes
* For price inquiries please email zebras@genedx.com