A full-likelihood method for the evaluation of causality of sequence variants from family data

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.

Figure  1

Two sample pedigrees used to demonstrate calculation of odds of causality (shown in table 1). Blackened symbols indicate affected individuals; question marks (?) indicate phenotype changed in table 1; plus (+) and minus (−) symbols indicate carrier status at the sequence variant under assessment. Numbers are given for those individuals specifically referred to in table 1.