Genetic anticipation. Expanding tandem repeats.
The recent discovery that expanding trinucleotide repeats are a form of mutation is a radical departure from the traditional genetic principles of inheritance based on the stable transmission of DNA sequences. The concept that a gene may be altered from tissue to tissue in a single individual or from one generation to the next and that it may confer increasing mutability on itself has provided some insight into the phenomenon of anticipation as manifested by increasing severity, declining age of onset, and increasing penetrance in several inherited disorders. This concept raises the question of how common this mutational mechanism may be in the causes of genetic disease. For example, expansions of trinucleotide repeats may be the underlying mechanism for other disorders that show features suggestive of anticipation such as schizophrenia, bipolar affective disorder, autism and other hereditary ataxias. Expressed genes with trinucleotide repeats have been observed in fetal and adult brains. A recent approach to identifying expanded repeats may simplify the process of finding candidate genes. It is intriguing to speculate how often observations such as intrafamilial variation and even new mutations may be due to such a mechanism. Systematic studies of families with disorders found to be associated with such repeats will be necessary. The implications in genetic counseling for prediction of postnatal outcome as well as risks of recurrence are truly staggering. Meanwhile, the immediate benefit of the knowledge of trinucleotide repeat expansions concerning the six disorders discussed will be the application of direct methods of diagnosis avoiding linkage analysis. The long-term benefits may very well be the discovery of more effective treatment modalities based on correction of the gene defects. Exciting times for human genetics appear to be at hand.