Fragile X syndrome genotype-phenotype correlations

Mutation type	Number of CGG trinucleotide repeats	Methylation status of FMR1	Clinical status
Mutation type	Number of CGG trinucleotide repeats	Methylation status of FMR1	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.

Reference:

Riddle JE, Cheema A, Sobesky WE, et al. Phenotypic involvement in females with the FMR1 gene mutation. Am J Ment Retard. 1998; 102:590.
Bourgeois JA, Coffey SM, Rivera SM, et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 2009; 70:852.
Hunter JE, Abramowitz A, Rusin M, Sherman SL. Is there evidence for neuropsychological and neurobehavioral phenotypes among adults without FXTAS who carry FMR1 premutation? A review of current literature. Genet Med 2009; 11:79.
Chonchaiya W, Nguyen DV, Au J, et al. Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome. Clin Genet 2010; 78:38.
Wheeler A, Raspa M, Hagerman R, et al. Implications of the FMR1 premutation for children, adolescents, adults, and their families. Pediatrics 2017; 139:S172.
Hagerman RJ, Protic D, Rajaratnam A, et al. Fragile X-associated neuropsychiatric disorders (FXAND). Front Psychiatry 2018; 9:564.

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).

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Fragile X syndrome genotype-phenotype correlations