premutations

A premutation is an allele of a gene that contains an expanded repeat length beyond the normal range but is not large enough to cause disease in the carrier. In the context of trinucleotide or other short-tandem-repeat expansion disorders, premutations lie in an intermediate zone between normal alleles and full disease-causing expansions. The concept is best described for the FMR1 gene, where a CGG trinucleotide repeat determines Fragile X status.

In FMR1, normal alleles typically have about 5–44 CGG repeats. Premutation alleles generally range from about 55 to 200 repeats, although exact thresholds can vary by assay. Alleles in the intermediate/gray zone (roughly 45–54 repeats) are considered at the edge of normal. Full mutations, exceeding about 200 repeats, cause Fragile X syndrome. Premutations do not usually cause the classic Fragile X syndrome themselves, but some carriers develop related conditions later in life.

Mechanistically, premutations can produce disease via RNA-mediated toxicity rather than loss of the encoded protein. In FMR1 premutation carriers, FMR1 mRNA levels are elevated, while the FMRP protein may be reduced or modestly affected. Clinically, premutations are associated with Fragile X-associated tremor/ataxia syndrome (FXTAS) in older male carriers and Fragile X–associated primary ovarian insufficiency (FXPOI) in female carriers; carriers can also show milder neuropsychiatric or cognitive features.

Genetic testing uses PCR and, when needed, Southern blot to determine CGG repeat length. Counseling emphasizes transmission risk: premutations are prone to expanding to full mutations in offspring, especially with maternal transmission.