Direct detection of FMR1 CGG repeats causative for fragile X syndrome coupled with 24-chromosome aneuploidy screening in single cells

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

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

Genes ◽

10.3390/genes11020136 ◽

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.

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Early Intervention Combined with Targeted Treatment Promotes Cognitive and Behavioral Improvements in Young Children with Fragile X Syndrome

Case Reports in Genetics ◽

10.1155/2012/280813 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 15

Author(s):

Tri Indah Winarni ◽

Andrea Schneider ◽

Mariya Borodyanskara ◽

Randi J. Hagerman

Keyword(s):

Young Children ◽

Fragile X Syndrome ◽

Dendritic Spine ◽

Environmental Enrichment ◽

Fragile X ◽

Educational Interventions ◽

Targeted Treatment ◽

Pharmacological Intervention ◽

Cgg Repeats ◽

And Behavior

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability due to an expansion in the full mutation range (>200 CGG repeats) of the promoter region of theFMR1gene leading to gene silencing. Lack of FMRP, a critical protein for dendritic spine formation and maturation, will cause FXS. Early environmental enrichment combined with pharmacological intervention has been proven to rescue dendritic spine abnormalities in the animal model of FXS. Here we report on 2 young children with FXS who were treated early with a combination of targeted treatment and intensive educational interventions leading to improvement in their cognition and behavior and a normal IQ.

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Epstein-Barr Virus Transformation of Human Lymphoblastoid Cells from Patients with Fragile X Syndrome Induces Variable Changes on CGG Repeats Size and Promoter Methylation

Molecular Diagnosis ◽

10.1007/bf03260033 ◽

2003 ◽

Vol 7 (3) ◽

pp. 163-167 ◽

Cited By ~ 6

Author(s):

Victoria Bonilla ◽

Francisco Sobrino ◽

Miguel Lucas ◽

Elizabeth Pintado

Keyword(s):

Fragile X Syndrome ◽

Promoter Methylation ◽

Epstein Barr Virus ◽

Fragile X ◽

Lymphoblastoid Cells ◽

Barr Virus ◽

Cgg Repeats ◽

Virus Transformation ◽

Epstein Barr

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Simplified Molecular Diagnosis of Fragile X Syndrome by Fluorescent Methylation-Specific PCR and GeneScan Analysis

Clinical Chemistry ◽

10.1373/clinchem.2006.068593 ◽

2006 ◽

Vol 52 (8) ◽

pp. 1492-1500 ◽

Cited By ~ 30

Author(s):

Youyou Zhou ◽

Josephine MS Lum ◽

Gare-Hoon Yeo ◽

Jennifer Kiing ◽

Stacey KH Tay ◽

...

Keyword(s):

Fragile X Syndrome ◽

Southern Blot ◽

Molecular Diagnosis ◽

Blot Analysis ◽

Southern Blot Analysis ◽

Fragile X ◽

Molecular Diagnostic ◽

Methylation Specific Pcr ◽

Specific Pcr ◽

Cgg Repeats

Abstract Background: Fragile X syndrome (FXS), the most common cause of inherited mental impairment, is most commonly related to hyperexpansion and hypermethylation of a polymorphic CGG trinucleotide repeat in the 5′ untranslated region of the FMR1 gene. Southern blot analysis is the most commonly used method for molecular diagnosis of FXS. We describe a simplified strategy based on fluorescent methylation-specific PCR (ms-PCR) and GeneScan™ analysis for molecular diagnosis of fragile X syndrome. Methods: We used sodium bisulfite treatment to selectively modify genomic DNA from fragile X and normal lymphoblastoid cell lines and from patients. We then performed ms-PCR amplification using fluorescently-labeled primers complementary to modified methylated or unmethylated DNA. Amplification products were resolved by capillary electrophoresis. FMR1 mutational status was determined by a combination of fluorescent peak sizes and patterns on the GeneScan electropherogram. Results: DNA samples from male and female persons with known NL, PM, and FM FMR1 CGG repeats were analyzed. Each FMR1 genotype produced a unique GeneScan electropherogram pattern, thus providing a way to identify the various disease states. The number of CGG repeats in all NL and PM alleles were determined accurately. Analysis by both the new assay and Southern blot of a family segregating with FXS showed complete concordance between both methods. Conclusions: This simplified molecular diagnostic test, based on fluorescent methylation-specific PCR, may be a suitable alternative or complement to Southern blot analysis for the diagnosis of FXS.

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Common Variant Associations with Fragile X Syndrome

10.1101/115998 ◽

2017 ◽

Author(s):

James J Crowley ◽

Jin Szatkiewicz ◽

Anna K Kähler ◽

Paola Giusti-Rodriguez ◽

NaEshia Ancalade ◽

...

Keyword(s):

Fragile X Syndrome ◽

Odds Ratio ◽

De Novo ◽

Fragile X ◽

De Novo Mutation ◽

Risk Haplotype ◽

Functional Genomic ◽

Cgg Repeats ◽

Genome Wide ◽

Protective Haplotype

AbstractFragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5×10−10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13×l0−14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75×10−5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders.

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New Targeted Treatments for Fragile X Syndrome

Current Pediatric Reviews ◽

10.2174/1573396315666190625110748 ◽

2019 ◽

Vol 15 (4) ◽

pp. 251-258 ◽

Cited By ~ 1

Author(s):

Dragana Protic ◽

Maria J. Salcedo-Arellano ◽

Jeanne Barbara Dy ◽

Laura A. Potter ◽

Randi J. Hagerman

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Behavioral Problems ◽

Rna Binding ◽

Fragile X ◽

Symptomatic Treatment ◽

Fmr1 Gene ◽

Fragile X Mental Retardation ◽

Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

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