Identical mutations and phenotypic variation

Abstract

The relationship between pathogenetic mutations and disease phenotype is becoming increasingly complex. Well-delineated clinical entities can be genetically heterogeneous, and mutations in a particular gene may result in fundamental clinical differences. Genetic heterogeneity includes mutations at different gene loci or allelic mutations within a single gene, resulting in a similar phenotype. However, one and the same mutation is expected to be associated with a uniform clinical picture. In the present article, evidence is presented that this is not necessarily the case, and examples of identical mutations resulting in highly variable combinations of clinical features are discussed. Although the number of examples of this puzzling phenomenon is rapidly increasing, the underlying mechanisms are as yet poorly understood. In some cases, interacting genetic alterations can be held responsible for the phenotypic heterogeneity; in others, epigenetic phenomena provide a plausible explanation. These and other mechanisms under discussion are considered here. The Mendelian concept of monofactorial disease causation appears to be increasingly untenable for a growing number of developmental errors.