New Mutations and Phenocopies

Abstract

The rules stated at the conclusion of the preceding chapter apply only when the specific disease in the family seeking advice is demonstrably subject to the autosomal-dominant mode of inheritance. Frequently, however, the symptoms of the proband will be identical to those observed in other families with the same anomaly in which the autosomal-dominant mode has been definitely established. Yet even the most painstaking research has failed to discover any further cases in the proband’s family; of particular importance is the fact that there is nothing wrong with either of his parents. In situations of this kind, one of four explanations usually applies:

• 1. There is a phenotypically similar or identical disease that is subject to the autosomal-recessive mode of inheritance. Because we have apparently identical diseases with different modes of inheritance, we speak of “genetic heterogeneity,” and this phenomenon is all too frequent. Whether this explanation is the correct one must be decided individually from case to case with the aid of knowledge derived from specialized genetic research publications. Should study of the relevant literature show that the problem is as yet unresolved because of insufficient research data, another factor that would point to the autosomal-recessive mode would be some degree of consanguinity between the parents, e.g., they are cousins. But, again, should the parents be unrelated, this does not exclude the possibility of an autosomal-recessive form of the anomaly. Fortunately, since there is no simple way of distinguishing the forms otherwise, there is a great deal of research literature dealing with the more common? defects that are subject to both modes and establishing the factors which differentiate the autosomal-recessive forms from the autosomal-dominants.

• 2. The second possibility is that of incomplete penetrance (see Chapter 3). In such a case, the trait, even if the parents seem unaffected, will be in evidence among the closer relatives such as siblings, grandparents, etc.