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A Full-likelihood Method for the Evaluation of Causality of Sequence Variants from Family Data

Overview
Journal Am J Hum Genet
Publisher Cell Press
Specialty Genetics
Date 2003 Aug 6
PMID 12900794
Citations 65
Authors
Deborah Thompson
Douglas F Easton
David E Goldgar
Affiliations
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Abstract

In many disease genes, a substantial fraction of all rare variants detected cannot yet be used for genetic counselling because of uncertainty about their association with disease. One approach to the characterization of these unclassified variants is the analysis of patterns of cosegregation with disease in affected carrier families. Petersen et al. previously provided a simplistic Bayesian method for evaluation of causality of such sequence variants. In the present report, we propose a more general method based on the full pedigree likelihood, and we show that the use of this method can provide more accurate and informative assessment of causality than could the previous method. We further show that it is important that the pedigree information be as complete as possible and that the distinction be made between unaffected individuals and those of unknown phenotype.

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References
1.
Orelli B, Logsdon Jr J, Bishop D . Nine novel conserved motifs in BRCA1 identified by the chicken orthologue. Oncogene. 2001; 20(32):4433-8. DOI: 10.1038/sj.onc.1204485. View
2.
Frank T, Deffenbaugh A, Reid J, Hulick M, Ward B, Lingenfelter B . Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002; 20(6):1480-90. DOI: 10.1200/JCO.2002.20.6.1480. View
3.
Lathrop G, Lalouel J, Julier C, Ott J . Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984; 81(11):3443-6. PMC: 345524. DOI: 10.1073/pnas.81.11.3443. View
4.
Petersen G, Parmigiani G, Thomas D . Missense mutations in disease genes: a Bayesian approach to evaluate causality. Am J Hum Genet. 1998; 62(6):1516-24. PMC: 1377150. DOI: 10.1086/301871. View
5.
Easton D, Bishop D, Ford D, Crockford G . Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993; 52(4):678-701. PMC: 1682082. View