Dynamic mutations and psychiatric genetics

In the past 3 years, a novel class of pathogenic mutation has seized the attention of geneticists. Socalled 'dynamic mutations', caused by expanding trinucleotide repeats, are responsible for the pathogenesis of a growing list of disorders, including fragile X syndrome and Huntington's disease. In addition to a shared molecular mechanism, trinucleotide repeat diseases also share a number of clinical features. CNS involvement occurs in all these disorders, usually in the form of mental handicap or neurodegeneration. However, their most striking feature is variation in penetrance and expressivity even in different members of the same family. In some cases such as fragile X syndrome this variability can be extreme with the clinical phenotype ranging from essentially unaffected (nonpenetrant) to profoundly disabled. In others such as Huntington's disease, it is more subtle and restricted to differences in age of onset between generations. The functional psychoses can also be considered highly heritable CNS disorders that show variable penetrance and expressivity (McGuffin et al. 1994) and dynamic mutations have recently been proposed as explanations for the complex genetic transmission of both schizophrenia (Asherson el al. 1994; Bassett et al. 1994), and manic depressive illness (Mclnnis et al. 1993). In this review, we will give an overview of the genetics of trinucleotide repeat diseases and critically review the evidence that may implicate this class of mutation in the genetic aetiologies of manic depressive illness and schizophrenia.