Classification of Missense Mutations of Disease Genes.

Journal Article (Journal Article)

Clinical management of individuals found to harbor a mutation at a known disease-susceptibility gene depends on accurate assessment of mutation-specific disease risk. For missense mutations (MMs)-mutations that lead to a single amino acid change in the protein coded by the gene-this poses a particularly challenging problem. Because it is not possible to predict the structural and functional changes to the protein product for a given amino acid substitution, and because functional assays are often not available, disease association must be inferred from data on individuals with the mutation. Inference is complicated by small sample sizes and by sampling mechanisms that bias toward individuals at high familial risk of disease. We propose a Bayesian hierarchical model to classify the disease association of MMs given pedigree data collected in the high-risk setting. The model's structure allows simultaneous characterization of multiple MMs. It uses a group of pedigrees identified through probands tested positive for known disease associated mutations and a group of test-negative pedigrees, both obtained from the same clinic, to calibrate classification and control for potential ascertainment bias. We apply this model to study MMs of breast-ovarian susceptibility genes BRCA1 and BRCA2, using data collected at the Duke University Medical Center in Durham, North Carolina.

Full Text

Duke Authors

Cited Authors

  • Zhou, X; Iversen, ES; Parmigiani, G

Published Date

  • January 2005

Published In

Volume / Issue

  • 100 / 469

Start / End Page

  • 51 - 60

PubMed ID

  • 18418466

Pubmed Central ID

  • PMC2311507

Electronic International Standard Serial Number (EISSN)

  • 1537-274X

International Standard Serial Number (ISSN)

  • 0162-1459

Digital Object Identifier (DOI)

  • 10.1198/016214504000001817


  • eng