Penetrance rate estimation in autosomal dominant conditions

Abstract

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.

Keywords: genetic counseling; maximum likelihood method; penetrance rate; recurrence risks.

Figure 1

Filtered pedigree of a family with several cases of an incompletely penetrant autosomal disease.

Figure 2

Pedigree containing a grouped tree of normal individuals (modified from Majewski et al., 1985).

Figure 3

Hypothetical pedigree containing a grouped tree of normal individuals with incomplete information (at left) and the possible configurations obtained from the grouped tree (at right).

Figure 4

Probabilities associated with all possible trees of offspring size = 2, in which the pedigree generator is an obligate carrier of a pathologic gene. The pedigree generator is affected in the first three trees and unaffected in the remaining ones.

Figure 5

Relation between unbiased (K) and biased (K’) penetrance values, shown at abscissa and ordinate axes respectively, depending on offspring size (2, 3, 4, 5, 6, ..., infinite).