The fragile X syndrome and other fragile site disorders.

Abstract

Dynamic mutations are caused by amplification of a trinucleotide or other simple sequence repeat, which leads to disease and/or expression of a fragile site (Richards and Sutherland 1992). In contrast to the mendelian inheritance observed in most hereditary disorders caused by point mutations, deletions, insertions, or duplications, dynamic mutations show non-mendelian inheritance, as the amplified repeat expands or, more rarely, contracts when transmitted from one generation to the next. In the normal population, these simple sequence repeats are small, but polymorphic, having a different length. Repeats in the normal size range are stably transmitted from one generation to the next. However, a minority of individuals have larger repeats that are meiotically unstable and generally expand upon transmission from one generation to the next. If the dynamic mutation causes disease, this progressive amplification is reflected in increasing frequency and severity of the disease in successive generations. When the repeat is below a specific threshold size in an individual of the older generations of the family, the disease may not manifest itself at all. However, when the repeat exceeds a threshold size in the progeny, the disease symptoms become clear. This phenomenon of increased disease severity with successive generations, characteristic of dynamic mutations, is called anticipation.KeywordsFragile SiteFull MutationDynamic MutationPremutation AlleleJacobsen SyndromeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.