Fragile X syndrome is an inherited disorder caused by a CGG repeat expansion in the FMR1 gene. The syndrome is characterized by mild-to-severe mental retardation, which may be associated with behavioural disturbances and typical physical signs. As being X-linked, the syndrome shows its typical manifestations in males, although some females may be mildly symptomatic. The syndrome is caused, in most cases, by an expansion of 200 or more CGG triplet repeats in the FMR1 gene (full mutation). Alleles of lower size may represent a concern for geneticists and genetic counselors, especially when it comes to assess the reproductive risk for carriers.
Fragile X syndrome is caused by an expansion of 200 or more CGG triplet repeats in the FMR1 gene (full mutation). Much more rarely the syndrome can be caused by other types of mutations in the same gene. Almost always, extensive somatic variation of repeat number is observed in a peripheral blood specimen of a patient with a full mutation. As a result, laboratories may report this somatic variation as a range of several hundred repeats. The full mutation causes a loss of function of the protein, as it inhibits or reduces the gene transcription. The full mutation is usually accompanied by hypermethylation of the deoxycytosine residues in the promoter of the gene and gives rise to the expression of the cytogenetic fragile site called FRAXA.
FMR1 alleles with 55 to 200 repeats are classified as premutation. Because of the so called anticipation phenomenon, a premutation can expand into a full mutation in the transmission to the offsrping. Premutation carriers are thereore at inreased risk of having a child affected by fragile X syndrome. Premutations are also at increased risk of developing fragile X tremor/ataxia syndrome (FXTAS) or premature ovarian insufficiency (POI). Fragile X tremor/ataxia syndrome is completely different from fragile X syndrome (premutation alleles cause a gain of function rather than a loss of function of the protein). Fragile X tremor/ataxia syndrome typically affects males and is variabily characterized by progressive intentional tremor with adult onset (typically in the sixth decade), ataxic gait, white matter lesions on MRI, memory and cognitive decline, and muscle weakness. Some females may be mildly affected. Premature ovarian insufficiency (POI) consists in the cessation of menses before 40 years and occurs in approximately 20% of females who have an FMR1 premutation. Patients with a FMR1 premutation and some clinical signs of fragile X syndrome have been reported.
Alleles with 45 to 54 repeats are classified as intermediate alleles (or “grey-zone” alleles / borderline alleles). These alleles can be of concern for geneticists and genetic counselors, especially when it comes to assess the reproductive risk for carriers. The number of counseling requests for this kind of alleles has increased since the spreading of preconceptional/prenatal carrier screenings, as the FMR1 gene is included in most of these tests.
The point is that intermediate alleles do not cause fragile X syndrome nor do they confer an increased risk of having a child affected by fragile X syndrome. Acutally, intermediate alleles can be further subdivided in two categories: alleles from 45 to 49 repeats and alleles from 50 to 54 repeats. Also intermediate alleles may be subject to anticipation and expand in the transmission to offspring. However, alleles from 45 to 49 have been so far reported to expand of maximum 1 to 2 CGG repeats. While alleles in the range from 50 to 54 may expand into the premutation range, none of these alleles has been so far reported to expand into full mutation.