Genotype-phenotype correlations in von Hippel-Lindau (VHL) disease: Predisposition to pheochromocytoma
- Cambridge Univ. (United Kingdom); and others
VHL disease is a dominantly inherited familial cancer syndrome predisposing to a variety of neoplasms, most frequently retinal and CNS haemangioblastoma, renal cell carcinoma, and pheochromocytoma. Marked interfamilial differences in predisposition to pheochromocytoma are recognized. We identified germline mutations in 85 unrelated VHL disease patients (22 large germline deletions, 44 different intragenic mutations: 21 missense, 6 nonsense, 16 deletions or insertions, 1 splice donor site mutation), and correlated this information with phenotype in 65 kindreds. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma but only 2 of 12 families with pheochromocytoma ({chi}{sup 2}=12.33 p<0.01). Of 12 families with pheochromocytoma, 10 had missense mutations compared to 13 of 53 kindreds without pheochromocytoma ({chi}{sup 2}=12.33 p<0.001). 5% of kindreds with large deletions or intragenic mutations predicted to cause a truncated protein were pheochromocytoma positive, compared to 43% of kindreds with misense mutations. In particular, substitution of an arginine at codon 238 (Arg{yields}Trp or Arg{yields}Gln) was associated with a high risk (62%) of pheochromocytoma. The identification of germline mutations in VHL disease not only allows presymptomatic diagnosis, but can also indicate the risk of pheochromocytoma. In addition these results provide a basis for screening for VHL gene mutations in patients with familial or sporadic pheochromocytoma. To date, VHL gene mutations have been identified in 2 families with familial pheochromocytoma.
- OSTI ID:
- 133400
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0128
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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