Special Issue "Fragile X Syndrome Genetics"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 15 February 2022.

Special Issue Editors

Prof. David E. Godler
E-Mail Website
Guest Editor
1. Diagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia
2. Faculty of Medicine, Dentistry and Health Sciences, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
Interests: genomics; fragile X syndrome; FMR1; FMRP; CGG; epigenetics; imprinting disorders; cohort studies; clinical trials
Special Issues and Collections in MDPI journals
Prof. Dr. William Ted Brown
E-Mail Website
Co-Guest Editor
1. Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia
2. Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
Interests: developmental disabilities; fragile X syndrome; FMR1; FMRP; autism; progeria; aging; treatment trials

Special Issue Information

Dear Colleagues,

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading single-gene cause of autism. FXS is usually caused by a CGG trinucleotide expansion to greater than 200 repeats, inducing epigenetic silencing of the fragile X gene, FMR1, and loss of its protein product, FMRP, essential for normal neurodevelopment. Since the discovery of the causative mechanism of FXS around 1991, there has been rapid progress in better understanding FXS neurogenetics and developing improved diagnostic and screening techniques, as well as potential targeted therapies. Preclinical trials that assessed treatments for pathways dysregulated due to loss of FMRP were highly successful in FMR1 knockout mouse models. Unfortunately, successful treatment trials in mice have not had similar improved outcomes in FXS patient trials. One possible explanation for the lack of translation of the preclinical success is that KO mouse models do not fully reflect the underlying biology of FXS in humans where mosaicism for active and inactive alleles plays a significant role.  

This Special Issue will comprise reviews and original research articles focused on the recent advances in genetics/genomics testing; the contribution of mosaicism and epigenetic processes; and the clinical description, co-morbidities, biomarkers, and natural history of FXS. Current and future directions with a focus on improved screening, diagnosis, and treatment will be addressed in this issue.

Prof. David E. Godler
Prof. Dr. William Ted Brown
Guest Editors

Manuscript Submission Information

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Keywords

  • fragile X syndrome
  • FMR1
  • FMRP
  • mosaicism
  • fragile X intellectual disability
  • autism and fragile X
  • fragile X biomarkers
  • fragile X treatment trials

Published Papers (3 papers)

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Research

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Article
Development of a Quantitative FMRP Assay for Mouse Tissue Applications
Genes 2021, 12(10), 1516; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101516 - 26 Sep 2021
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Abstract
Fragile X syndrome results from the absence of the FMR1 gene product—Fragile X Mental Retardation Protein (FMRP). Fragile X animal research has lacked a reliable method to quantify FMRP. We report the development of an array of FMRP-specific monoclonal antibodies and their application [...] Read more.
Fragile X syndrome results from the absence of the FMR1 gene product—Fragile X Mental Retardation Protein (FMRP). Fragile X animal research has lacked a reliable method to quantify FMRP. We report the development of an array of FMRP-specific monoclonal antibodies and their application for quantitative assessment of FMRP (qFMRPm) in mouse tissue. To characterize the assay, we determined the normal variability of FMRP expression in four brain structures of six different mouse strains at seven weeks of age. There was a hierarchy of FMRP expression: neocortex > hippocampus > cerebellum > brainstem. The expression of FMRP was highest and least variable in the neocortex, whereas it was most variable in the hippocampus. Male C57Bl/6J and FVB mice were selected to determine FMRP developmental differences in the brain at 3, 7, 10, and 14 weeks of age. We examined the four structures and found a developmental decline in FMRP expression with age, except for the brainstem where it remained stable. qFMRPm assay of blood had highest values in 3 week old animals and dropped by 2.5-fold with age. Sex differences were not significant. The results establish qFMRPm as a valuable tool due to its ease of methodology, cost effectiveness, and accuracy. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Review

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Review
Mechanisms of Genome Instability in the Fragile X-Related Disorders
Genes 2021, 12(10), 1633; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101633 - 17 Oct 2021
Viewed by 291
Abstract
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that [...] Read more.
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Other

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Case Report
Detection of Cryptic Fragile X Full Mutation Alleles by Southern Blot in a Female and Her Foetal DNA via Chorionic Villus Sampling, Complicated by Mosaicism for 45,X0/46,XX/47,XXX
Genes 2021, 12(6), 798; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060798 - 24 May 2021
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Abstract
We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55–199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG [...] Read more.
We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55–199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG > 200), that causes FXS through hypermethylation of the FMR1 promoter. The CGG sizing analysis in this study used AmplideX triplet repeat primed polymerase chain reaction (TP-PCR) and long-range methylation sensitive PCR (mPCR). These methods detected a 73 CGG PM allele in the proband’s blood, and a 164 CGG PM allele in her male cultured chorionic villus sample (CVS). In contrast, the Southern blot analysis showed mosaicism for: (i) a PM (71 CGG) and an FM (285–768 CGG) in the proband’s blood, and (ii) a PM (165 CGG) and an FM (408–625 CGG) in the male CVS. The FMR1 methylation analysis, using an EpiTYPER system in the proband, showed levels in the range observed for mosaic Turner syndrome. This was confirmed by molecular and cytogenetic karyotyping, identifying 45,X0/46,XX/47,XXX lines. In conclusion, this case highlights the importance of Southern blot in pre- and postnatal testing for presence of an FM, which was not detected using AmplideX TP-PCR or mPCR in the proband and her CVS. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Development of a quantitative FMRP assay for mouse tissue applications

2. Mechanisms of genome instability in the Fragile X-related disorders

3. Beyond trinucleotide repeat expansion in Fragile X syndrome: rare coding and non-coding variants in FMR1 and associated phenotypes

4. Behaviour problems and social competence in Fragile X Syndrome: A systematic review

5. Female FMR1 full-mutation patients: clinical and molecular characterization of a cohort of patients

 

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