Tissue mosaicism, <scp><i>FMR1</i></scp> expression and intellectual functioning in males with fragile X syndrome

Baker, Emma K.; Arpone, Marta; Bui, Minh; Kraan, Claudine; Ling, Ling; Francis, David; Hunter, Matthew; Rogers, Carolyn; Field, Michael; María, Lorena Santa; Faundes, Víctor; Curotto, Bianca; Morales, Patricio; Trigo, Cesar; Salas, Isabel; Alliende, Angelica M.; Amor, David J.; Godler, David E.

doi:10.1002/ajmg.a.63027

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…In fact, we found that 30-40% of FXS(M), who based on standard PCR and Southern Blot testing are considered full mutation, fully methylated, express trace levels of FMRP in their blood. This is consistent with ndings of incomplete silencing of the FMR1 gene reported by our group and others 2,17 . In each of our recent papers, we reported a small to medium sized correlation between Deviation IQ 18 and FMRP and mRNA levels 1,2 .…”

Section: Introductionsupporting

confidence: 94%

A Paradigm Shifting View of Intellectual Disability: A Near Normal Distribution of IQ in Fragile X Syndrome

Schmitt

Will

Shaffer

et al. 2023

Preprint

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Fragile X Syndrome (FXS) is an X-linked disorder leading to the loss of expression of FMR1-protein product, FMRP. The absence or deficiency of FMRP is thought to result in the characteristic FXS phenotypes, including intellectual disability. Identifying the relationship between FMRP levels and IQ may be critical to better understand underlying mechanisms and advance treatment development and planning. A sample of 80 individuals with FXS (67% male), aged 8–45 years, completed IQ testing and blood draw via venipuncture to determine the relationship between IQ scores and FMRP levels as well as the normalcy of IQ distributions. In females with FXS only, higher FMRP levels were associated with higher IQ. In contrast, males with FXS showed a downward shifted but otherwise normal distribution of IQ scores. Our findings offer a paradigm-shifting views of FXS—males with FXS have normally distributed IQ that is downshifted 5 standard deviations. Our novel work provides evidence of a “FXS standard curve”, and is a critical step towards establishing molecular markers of disease severity in FXS. There is much future work to better understand the mechanism by which FMRP loss leads to intellectual disability and what biological/genetic and socio-environmental factors contribute to variation in IQ.

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Section: Introductionsupporting

confidence: 94%

A Paradigm Shifting View of Intellectual Disability: A Near Normal Distribution of IQ in Fragile X Syndrome

Schmitt

Will

Shaffer

et al. 2023

Preprint

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“…The results obtained after mSB did not show an association between methylation in blood and intellectual disability. They demonstrated incomplete silencing of FMR1 in the patients with methylation mosaicism, which showed that MS-QMA gave superior results to mSB [40].…”

Section: Southern Blotmentioning

confidence: 98%

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome

Ciobanu

Nucă

Popescu

et al. 2023

IJMS

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The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice.

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“…In mosaicism of hypermethylation, some cells exhibit hypermethylation, and others do not. In cells in which fully mutated or premutated alleles are not methylated, the FMR1 gene is transcriptionally active and can be expressed [ 90 – 95 ]. In male individuals, the most frequent presentation of mosaicism is non-methylation of alleles with partial mutations and either methylation or non-methylation of alleles with full mutations (i.e., a combination of mosaicism of size and mosaicism of methylation) [ 14 ].…”

Section: Molecular and Phenotypic Variabilitymentioning

confidence: 99%

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

Elhawary,

AlJahdali,

Abumansour

et al. 2023

Hum Genomics

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This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome’s variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene’s promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS’s variable expressivity by regulating the pathophysiological mechanisms related to the syndrome’s behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

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Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

Cited by 3 publications

References 42 publications

A Paradigm Shifting View of Intellectual Disability: A Near Normal Distribution of IQ in Fragile X Syndrome

A Paradigm Shifting View of Intellectual Disability: A Near Normal Distribution of IQ in Fragile X Syndrome

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome

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

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