premutation

Premutation is a genetic term used to describe an allele that contains an elevated number of repeats in a gene relative to the normal population but is not large enough to cause the disease by itself. Premutations are typically unstable and can expand to a full mutation when passed on to the next generation. In many cases, the premutation carrier does not have the full disorder, though some individuals may show subtle or related clinical features.

The best-known example involves the FMR1 gene and Fragile X-related conditions. In Fragile X syndrome, the FMR1 CGG repeat is expanded beyond a normal range. Normal alleles usually have about 5 to 44 repeats, premutation alleles range roughly from 55 to 200 repeats, and full mutations exceed about 200 repeats, leading to gene silencing and the syndrome. Premutations can be associated with Fragile X–associated tremor/ataxia syndrome (FXTAS) in older male carriers and Fragile X–associated primary ovarian insufficiency (FXPOI) in female carriers, among other possible manifestations.

Transmission risk varies with repeat length and with the sex of the parent transmitting the allele. The chance of expansion from premutation to full mutation is higher when the premutation is transmitted by a mother; paternal transmission tends to show less expansion. Mosaicism can occur, with cells carrying different repeat lengths within the same individual.

Genetic testing for premutations typically uses PCR and, if needed, other methods to determine the exact repeat count. Counseling covers reproductive risk, uncertainty about expressivity, and options such as prenatal testing and assisted reproduction. Management focuses on symptom monitoring and supportive care, as there is no cure for the underlying repeat expansion.