The 'circular' problems of calculating risk: Dealing with consanguinity

Abstract

An ongoing problem in the genetics clinic is the calculation of inbreeding coefficients and recurrence risks for complex pedigrees, particularly when multiple 'loops' are present. Although the Human Genome Project promises information about more of our genes in the foreseeable future, the actual assignment of disease status to specific loci will continue at a slower pace, so that accurate risk calculations are needed. In the past few months several families with consanguinity were referred to us to confirm the calculations performed by the genetic counselor, and we became aware of some confusion in the field. We present here both (a) a clarification of definitions and concepts and (b) a review of how to perform the calculations, for several quantities (coefficient of relationship, coefficient of inbreeding, coefficient of kinship, and recurrence risk), in complex pedigrees. We discuss the availability of computer algorithms to assist in these calculations, and we encourage counselors to call on a reliable computer program for any but the simplest cases. At the same time, we reiterate our belief that computer algorithms do not relieve the counselor of the responsibility of knowing what to calculate and when.