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 POI and FXTAS
Methylated full mutation	>200	Completely methylated	100% with intellectual disability	Approximately 50% with intellectual disability, 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; POI: premature ovarian insufficiency; ID: intellectual disability; IQ: intelligence quotient.

* Both males and females with premutations and manifestations of some symptoms of fragile X syndrome have been reported^[1].

¶ FMR1 mutations are complex alterations involving nonclassic gene-disrupting alterations (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 mental retardation.

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.

Reproduced with permission from: Saul RA, Tarleton JC. FMR1-Related Disorders (August 2008). In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright © University of Washington, Seattle. 1997-2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=fragilex (Accessed on December 22, 2009).

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Fragile X syndrome genotype-phenotype correlations