Mutation type | Number of CGG trinucleotide repeats | Methylation status of FMR1 | Clinical status | |
Male | Female | |||
Premutation | Approximately 55 to 200 | Unmethylated | At risk for FXTAS* | At risk for FXPOI and FXTAS Potential increased risk of other fragile X-associated disorders* |
Full mutation | >200 | Completely methylated | 100% have ID | Approximately 50% with ID, approximately 50% normal intellect |
Repeat size mosaicism | Varies between premutation and full mutation in different cell lines | Partial: Unmethylated in the premutation cell line; methylated in the full mutation cell line | Nearly 100% affected with ID; may be higher functioning¶ than males with full mutation | Highly variable: Ranges from normal intellect to affected |
Methylation mosaicism | >200 | Partial: Mixture of methylated and unmethylated cell lines | Nearly 100% affected with ID; may be higher functioning¶ than males with full mutation | Highly variable: Ranges from normal intellect to affected |
Unmethylated full mutation | >200 | Unmethylated | Nearly all have ID but often have high functioning ID to low-normal intellect | Highly variable: Ranges from normal intellect to affected |
CGG: cytosine-guanine-guanine; FMR1: fragile X mental ribonucleoprotein 1; FXTAS: fragile X-associated tremor/ataxia syndrome; FXPOI: fragile X-associated primary ovarian insufficiency; ID: intellectual disability; IQ: intelligence quotient; ADHD: attention deficit hyperactivity disorder.
* Both males and females with premutations have been reported to have slightly elevated rates of some manifestations of fragile X syndrome, such as facial features, behavioral problems, learning disabilities, ADHD, and anxiety[1-4]. Some studies also indicate an increased rate of additional outcomes, such as depression, pain disorders, autoimmune disorders, and other health outcomes[5,6].
¶ FMR1 pathogenic variants are complex alterations involving nonclassic gene-disrupting variants (trinucleotide repeat expansion) and abnormal gene methylation. This complexity at the gene level affects production of the FMR1 protein and may result in an atypical presentation in which affected individuals occasionally have an IQ above 70, the traditional demarcation denoting ID.Reproduced with permission from: Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 Disorders (November 2019). In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1384/ (Accessed on October 4, 2022).
Do you want to add Medilib to your home screen?