Genotype-phenotype correlations in VHL exon deletions

• Published in: American journal of medical genetics. Part A Vol. 149A; no. 10; pp. 2147 - 2151
• Main Authors: McNeill, Alisdair, Rattenberry, Eleanor, Barber, Richard, Killick, Pip, MacDonald, Fiona, Maher, Eamonn R.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2009; Wiley-Liss
• Subjects: Adrenal Gland Neoplasms - complications; Adrenal Gland Neoplasms - genetics; Biological and medical sciences; Carcinoma, Renal Cell - complications; Carcinoma, Renal Cell - genetics; Cerebellar Neoplasms - complications; Cerebellar Neoplasms - genetics; Cytoskeletal Proteins - genetics; DNA Mutational Analysis; exon; Exons - genetics; Fanconi Anemia Complementation Group D2 Protein - genetics; Gene Deletion; Genotype; Germ-Line Mutation; Hemangioblastoma - complications; Hemangioblastoma - genetics; Humans; Kidney Neoplasms - complications; Kidney Neoplasms - genetics; Kidneys; Medical genetics; Medical sciences; Nephrology. Urinary tract diseases; Phenotype; Pheochromocytoma - complications; Pheochromocytoma - genetics; renal cell carcinoma; Retinal Neoplasms - complications; Retinal Neoplasms - genetics; Tumors of the urinary system; von Hippel-Lindau Disease - classification; von Hippel-Lindau Disease - complications; von Hippel-Lindau Disease - genetics; Von Hippel-Lindau syndrome; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Chromosomal aberration; Correlation; Carcinoma; Cardiovascular disease; gene deletion; Vascular disease; Exon; Gene; Deletion; Genetics; Grawitz tumor; Kidney disease; Nervous system diseases; Urinary system disease; Typing; Phacomatosis; Von Hippel-Lindau syndrome; Genotype; Malignant tumor; Genetic disease; Von Hippel-Lindau disease; Eye disease; Phenotype; renal cell carcinoma; Central nervous system disease; Cancer
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.33023

Von Hippel‐Lindau (VHL) syndrome is a dominantly inherited familial cancer syndrome caused by mutations in the VHL gene. VHL syndrome displays marked variation in expression and analysis of genotype–phenotype correlations have led to the concept of four subtypes of VHL syndrome (Types 1, 2A–C). Type 2 subtypes of VHL syndrome are characterized by the presence of pheochromocytoma and the three Type 2 subtypes are associated with differing risks of hemangioblastoma and renal cell carcinoma (RCC). Type 2 VHL syndrome is usually associated with surface missense mutations. Type 1 VHL syndrome is most commonly caused by germline exon deletions and truncating mutations and is characterized by susceptibility to hemangioblastomas and RCC but not pheochromocytoma. Recently, it has been suggested that large VHL gene deletions involving C3orf10 (HSPC300) might be associated with a low risk of RCC. We have reviewed the molecular and clinical characteristics of 127 individuals with germline VHL gene deletions. Large VHL gene deletions associated with a contiguous loss of C3orf10 were associated with a significantly lower lifetime risk of RCC than deletions that did not involve C3orf10. The risks of hemangioblastomas were similar in both groups. These results add to the growing body of evidence suggesting that patients with VHL syndrome caused by large VHL deletions that include C3orf10 may be designated as having a specific subtype (Type 1B) of the disorder. © 2009 Wiley‐Liss, Inc.