Unusual Inheritance Patterns Due to Dynamic Mutation in Fragile X Syndrome

Abstract

Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to dynamic mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for dynamic mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the premutation range. Dynamic mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of dynamic mutation diseases.