Variable Expressivity in Fragile X Syndrome: Towards the Identification of Molecular Characteristics That Modify the Phenotype

Abstract

Fragile X syndrome (FXS), is an X-linked inherited genetic disease. FXS is the leading cause of inherited intellectual disability and autism in the world. Those affected are characterized by intellectual disability, language deficit, typical facies, and macroorchidism. Alterations in the FMR1 gene have been associated with FXS. The majority of people with this condition have an allele with an expansion of more than 200 repeats in a tract of CGGs within the 5ʹ untranslated region, and this expansion is associated with a hypermethylated state of the gene promoter. FXS has incomplete penetrance and variable expressivity. Intellectual disability is present in 100% of males and 60% of females. Autism spectrum disorder symptoms appear in 50% to 60% of males and 20% of females. Other characteristics such as behavioral and physical alterations have significant variations in presentation frequency. The molecular causes of the variable phenotype in FXS patients are becoming clear: these causes are related to the FMR1 gene itself and to secondary, modifying gene effects. In FXS patients, size and methylation mosaicisms are common. Secondary to mosaicism, there is a variation in the quantity of FMR1 mRNA and the protein coded by the gene Fragile Mental Retardation Protein (FMRP). Potential modifier genes have also been proposed, with conflicting results. Characterizing patients according to CGG expansion, methylation status, concentration of mRNA and FMRP, and genotypification for possible modifier genes in a clinical setting offers an opportunity to identify predictors for treatment response evaluation. When intervention strategies become available to modulate the course of the disease they could be crucial for selecting patients and identifying the best therapeutic intervention. The purpose of this review is to present the information available about the molecular causes of the variability of the expression incomplete penetrance and variable expressivity in FXS and their potential clinical applications.

The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes

“…Magnetic resonance imaging (MRI) studies have observed multiple differences in the neuroanatomy of male Fmr1 KO mice on a FVB but not in the B6 background (Paradee et al, 1999 ; Lai et al, 2016 ). In fact, in monogenic diseases like FXS, genetic and environmental factors have a great influence, and these do not translate in all patients with FXS displaying autistic behaviors and intellectual deficits ranging from mild learning disfunction to severe cognitive impairment (Payán-Gómez et al, 2021 ). This variation should be a lesson rather than a problem, since it can partially explain why it has been impossible to transfer successful animal preclinical studies into clinical practice (Dahlhaus, 2018 ).…”

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

“…For example, Fragile X syndrome is caused by the expansion of over 200 repeats in the CGG motif in the 5′UTR of FMR1 on the X chromosome, resulting in hypermethylation of the promoter, silencing the gene ( Hagerman et al, 2017 ). Fragile X exhibits incomplete penetrance and reduced expressivity, with 100% of males and 60% of females presenting with ID and 50–60% of males and 20% of females diagnosed with autism spectrum disorder (ASD) ( Payán-Gómez et al, 2021 ). Wild type (WT) alleles contain <44 CGG repeats, while full mutations in affected individuals typically have >200 repeats.…”

Phenotypic variability to medication management: an update on fragile X syndrome

“…So, FXAND refers to the neuropsychiatric problems that typically occur at an earlier age than FXTAS. Hence, the FMR1 premutation would exhibit variable expressivity and be associated with a wide spectrum of clinical phenotypes [ 78 ].…”

“…Mosaicism has been reported as a source of phenotypic variability in FXS patients of both sexes, with a higher frequency in male patients [ 78 ]. The prevalence of mosaicism in male FXS patients varies greatly, from 12 to 41% in the general population [ 79 ].…”

“…Notably, in individuals with FXS, mosaicism can be either in the size of the CGG repeat expansion or in hypermethylation of the CpG island [ 80 ]. A recent study has evaluated alterations in FMR1 function due to both types of mosaicism [ 78 ]. Because mosaic individuals with FXS produce some FMRP, they have milder cognitive and behavioral deficits than non-mosaic individuals with FXS [ 81 , 82 ].…”