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Review
. 2024 Mar 3;15(3):331.
doi: 10.3390/genes15030331.

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome

YeEun Tak  1   2 , Andrea Schneider  2   3 , Ellery Santos  1 , Jamie Leah Randol  3 , Flora Tassone  1   3 , Paul Hagerman  1   3 , Randi J Hagerman  1   2
Affiliations
Review

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome

YeEun Tak et al. Genes (Basel). .

Abstract

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Keywords: fragile X mosaicism; fragile X premutation; fragile X premutation-associated conditions; fragile X syndrome; unmethylated full mutation.

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Conflict of interest statement

RJH has been funded by Zynerba and Tetra pharma companies to carry out treatment trials in FXS.

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