scholarly journals Unique AGG Interruption in the CGG Repeats of the FMR1 Gene Exclusively Found in Asians Linked to a Specific SNP Haplotype

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Pornprot Limprasert ◽  
Janpen Thanakitgosate ◽  
Kanoot Jaruthamsophon ◽  
Thanya Sripo
Keyword(s):  
Genetic Background ◽  
Fragile X ◽  
Cgg Repeat ◽  
Direct Dna Sequencing ◽  
Asian Populations ◽  
Cgg Repeats ◽  
Normal Individuals ◽  
The Common ◽  
Almost All ◽  
Agg Interruptions

Fragile X syndrome (FXS) is the most common inherited intellectual disability. It is caused by the occurrence of more than 200 pure CGG repeats in the FMR1 gene. Normal individuals have 6–54 CGG repeats with two or more stabilizing AGG interruptions occurring once every 9- or 10-CGG-repeat blocks in various populations. However, the unique (CGG)6AGG pattern, designated as 6A, has been exclusively reported in Asians. To examine the genetic background of AGG interruptions in the CGG repeats of the FMR1 gene, we studied 8 SNPs near the CGG repeats in 176 unrelated Thai males with 19–56 CGG repeats. Of these 176 samples, we identified AGG interruption patterns from 95 samples using direct DNA sequencing. We found that the common CGG repeat groups (29, 30, and 36) were associated with 3 common haplotypes, GCGGATAA (Hap A), TTCATCGC (Hap C), and GCCGTTAA (Hap B), respectively. The configurations of 9A9A9, 10A9A9, and 9A9A6A9 were commonly found in chromosomes with 29, 30, and 36 CGG repeats, respectively. Almost all chromosomes with Hap B (22/23) carried at least one 6A pattern, suggesting that the 6A pattern is linked to Hap B and may have originally occurred in the ancestors of Asian populations.

scholarly journals FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1780
Author(s):  
Mark Roth ◽  
Lucienne Ronco ◽  
Diego Cadavid ◽  
Blythe Durbin-Johnson ◽  
Randi J. Hagerman ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Peripheral Blood ◽  
Fragile X ◽  
Repeat Expansion ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

2021 ◽  
Vol 12 ◽  
Author(s):  
Marwa Zafarullah ◽  
Blythe Durbin-Johnson ◽  
Emily S. Fourie ◽  
David R. Hessl ◽  
Susan M. Rivera ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Brain Area ◽  
Ultra Performance Liquid Chromatography ◽  
Primary Objective ◽  
Pcr Analysis ◽  
Mass Analyzer ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Metabolic Signatures

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55–200 CGG repeats; PM) in the fragile X mental retardation (FMR1) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development.

scholarly journals Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Areerat Hnoonual ◽  
Charunee Jankittunpaiboon ◽  
Pornprot Limprasert
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Fmr1 Gene ◽  
Normal Male ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Normal Controls

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

scholarly journals Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1669
Author(s):  
Cedrik Tekendo-Ngongang ◽  
Angela Grochowsky ◽  
Benjamin D. Solomon ◽  
Sho T. Yano
Keyword(s):  
Copy Number ◽  
Trinucleotide Repeat ◽  
De Novo ◽  
Fragile X ◽  
Copy Number Variants ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Testing Strategies ◽  
Cgg Repeats

FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.

scholarly journals Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 248
Author(s):  
Elisabetta Tabolacci ◽  
Roberta Pietrobono ◽  
Giulia Maneri ◽  
Laura Remondini ◽  
Veronica Nobile ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Fragile X ◽  
Rare Event ◽  
The Other ◽  
Fmr1 Gene ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Agg Interruptions

Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5’ UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56–200 CGGs; contractions of a maternal PM or FM are rare. Here, we describe two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele. The first boy inherited a 51 CGG allele (without AGG interruptions) from his mother, who carries a PM allele with 72 CGGs. The other boy inherited from his FM mother an unusual allele with 19 CGGs resulting from a deletion, removing 85 bp upstream of the CGG repeat. Given that transcription of the deleted allele was found to be preserved, we assume that the binding sites for FMR1 transcription factors are excluded from the deletion. Such unusual cases resulting in non-mosaic reduction of maternal CGG expansions may help to clarify the molecular mechanisms underlying the instability of the FMR1 gene.

Validation of Polymerase Chain Reaction–Based Assay to Detect Actual Number of CGG Repeats in FMR1 Gene in Indian Fragile X Syndrome Patients

2016 ◽  
Vol 32 (4) ◽  
pp. 371-378
Author(s):  
Madhumita Roy Chowdhury ◽  
Sandeepa Chauhan ◽  
Anjali Dabral ◽  
B. K. Thelma ◽  
Neerja Gupta ◽  
...  
Keyword(s):  
Indian Population ◽  
Fragile X ◽  
Molecular Genetic ◽  
Turnaround Time ◽  
Primary Objective ◽  
Carrier Status ◽  
Rapid Pcr ◽  
Cgg Repeats ◽  
Polymerase Chain ◽  
Agg Interruptions

Molecular genetic testing for fragile X (FX) is complicated due to the large variation in the size of CGG expansion. The aim of this study was to apply this new technique using AmplideX FMR1 PCR assay, which is considered a better diagnostic tool for detecting expanded alleles in Indian population. The primary objective was to identify the carrier status of females and to correlate the instability of premutation alleles in females with the repeat sizes. 24 children with FX based on rapid PCR and 29 female relatives of these patients were included. Out of the 29 females screened, those whose child (or children) was affected by FX, were all premutation carriers confirming their role in transmission. The smallest PM allele that expanded into FM in the next generation was 78 repeats and the smallest PM allele detected was 63 repeats, and when transmitted from mother to offspring remained in the premutation range. In 4 families, the repeat size of the allele reduced from PM to normal repeat numbers in their daughters and in 1 case to borderline PM range. Thus, apart from the reduced turnaround time, this PCR based assay offers advantage by its sensitivity to detect CGG repeats in the intermediate region and lower range of premutation alleles. It also provides added information of AGG interruptions, which may have an impact on the counseling of women with intermediate and PM alleles.

scholarly journals Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dale J. Annear ◽  
Geert Vandeweyer ◽  
Ellen Elinck ◽  
Alba Sanchis-Juan ◽  
Courtney E. French ◽  
...  
Keyword(s):  
Human Disease ◽  
Fragile X ◽  
Disease Genes ◽  
Cgg Repeat ◽  
Neurodevelopmental Disease ◽  
Repeat Units ◽  
Cgg Repeats ◽  
Repeat Expansions ◽  
Ataxia Syndrome ◽  
Strong Candidate

AbstractExpanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

scholarly journals Mechanisms of Genome Instability in the Fragile X-Related Disorders

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1633
Author(s):  
Bruce E. Hayward ◽  
Karen Usdin
Keyword(s):  
Genome Instability ◽  
Fragile Site ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Large Numbers ◽  
Structural Abnormalities ◽  
Chromosomal Fragility ◽  
Ataxia Syndrome

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.

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