Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in theFMR1 gene in eight fragile X patients

1999 ◽  
Vol 85 (3) ◽  
pp. 311-316 ◽  
Author(s):  
M. Grasso ◽  
F. Faravelli ◽  
C. Lo Nigro ◽  
P. Chiurazzi ◽  
M.P. Sperandeo ◽  
...  
Keyword(s):  
Fragile X ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Flanking Sequences

Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽  
1996 ◽  
Vol 97 (1) ◽  
pp. 122-126
Author(s):  
Randi J. Hagerman ◽  
Louise W. Staley ◽  
Rebecca O'Conner ◽  
Kellie Lugenbeel ◽  
David Nelson ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Size Range ◽  
Cpg Island ◽  
Fragile X ◽  
Learning Disabled ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Responsible Gene ◽  
Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

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 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.

scholarly journals Mosaicism for the fragile X syndrome full mutation and deletions within the CGG repeat of the FMR1 gene.

1996 ◽  
Vol 33 (4) ◽  
pp. 338-340 ◽  
Author(s):  
M Mila ◽  
S Castellvi-Bel ◽  
A Sanchez ◽  
C Lazaro ◽  
M Villa ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Full Mutation ◽  
Cgg Repeat

Fragile X full mutation alleles composed of few alleles: Implications for CGG repeat expansion

2007 ◽  
Vol 146A (1) ◽  
pp. 60-65 ◽  
Author(s):  
Sarah L. Nolin ◽  
Xiao-hua Ding ◽  
George E. Houck ◽  
W. Ted Brown ◽  
Carl Dobkin
Keyword(s):  
Fragile X ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Cgg Repeat

scholarly journals A Novel FMR1 PCR Method for the Routine Detection of Low Abundance Expanded Alleles and Full Mutations in Fragile X Syndrome

2010 ◽  
Vol 56 (3) ◽  
pp. 399-408 ◽  
Author(s):  
Stela Filipovic-Sadic ◽  
Sachin Sah ◽  
Liangjing Chen ◽  
Julie Krosting ◽  
Edward Sekinger ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Southern Blotting ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Clinical Samples ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Specific Pcr ◽  
Cgg Repeats ◽  
Pcr Technology

Abstract Background: Fragile X syndrome (FXS) is a trinucleotide-repeat disease caused by the expansion of CGG sequences in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. Molecular diagnoses of FXS and other emerging FMR1 disorders typically rely on 2 tests, PCR and Southern blotting; however, performance or throughput limitations of these methods currently constrain routine testing. Methods: We evaluated a novel FMR1 gene–specific PCR technology with DNA templates from 20 cell lines and 146 blinded clinical samples. The CGG repeat number was determined by fragment sizing of PCR amplicons with capillary electrophoresis, and results were compared with those for FMR1 Southern blotting analyses with the same samples. Results: The FMR1 PCR accurately detected full-mutation alleles up to at least 1300 CGG repeats and consisting of >99% GC character. All categories of alleles detected by Southern blotting, including 66 samples with full mutations, were also identified by the FMR1 PCR for each of the 146 clinical samples. Because all full mutation alleles in samples from heterozygous females were detected by the PCR, allele zygosity was reconciled in every case. The PCR reagents also detected a 1% mass fraction of a 940-CGG allele in a background of 99% 23-CGG allele—a roughly 5- fold greater sensitivity than obtained with Southern blotting. Conclusions: The novel PCR technology can accurately categorize the spectrum of FMR1 alleles, including alleles previously considered too large to amplify; reproducibly detect low abundance full mutation alleles; and correctly infer homozygosity in female samples, thus greatly reducing the need for sample reflexing to Southern blotting.

scholarly journals Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation

2014 ◽  
Vol 206 (5) ◽  
pp. 599-607 ◽  
Author(s):  
Jeannine Gerhardt ◽  
Nikica Zaninovic ◽  
Qiansheng Zhan ◽  
Advaitha Madireddy ◽  
Sarah L. Nolin ◽  
...  
Keyword(s):  
Replication Origin ◽  
Fragile X ◽  
Embryonic Stem ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Single Nucleotide ◽  
Cgg Repeat ◽  
Cis Acting ◽  
Replication Fork Progression ◽  
The Relationship

Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a single-nucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.

scholarly journals A Homogeneous Assay for Analysis of FMR1 Promoter Methylation in Patients with Fragile X Syndrome

2007 ◽  
Vol 53 (4) ◽  
pp. 790-793 ◽  
Author(s):  
Christina Dahl ◽  
Karen Grønskov ◽  
Lars A Larsen ◽  
Per Guldberg ◽  
Karen Brøndum-Nielsen
Keyword(s):  
Fragile X Syndrome ◽  
Southern Blot ◽  
Cpg Island ◽  
Fragile X ◽  
Methylation Status ◽  
Melting Peak ◽  
Melting Curve Analysis ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Male Patients

Abstract Background: Fragile X syndrome is caused by the expansion of a CGG trinucleotide repeat at the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). When expanded to >200 repeats (full mutation), the repeat region and the adjacent promoter CpG island become hypermethylated, rendering FMR1 transcriptionally inactive. Conventional molecular diagnosis of fragile X syndrome involves determination of the CGG repeat number by Southern blot analysis. Methods: A homogeneous methylation-specific melting curve analysis (MS-MCA) assay for methylation status of the FMR1 promoter region was developed on the LightCycler platform. Genomic DNA was treated with sodium bisulfite, and a region containing 8 CpG sites was amplified in the presence of SYBR Green I, using primers that do not differentiate between methylated and unmethylated FMR1 molecules. After amplification, the samples were melted at 0.05 °C/s, and fluorescence melting curves were recorded. We studied samples, previously characterized by Southern blot analyses, from 10 female and 10 male donors with normal numbers of CGG trinucleotide repeats, 9 male donors who were premutation carriers, 4 male donors who carried both a premutation and a full mutation, and 25 patients with fragile X syndrome. Results: Samples from all 20 male patients with fragile X syndrome showed a high melting peak corresponding to fully methylated FMR1, whereas samples from healthy males showed a single low melting peak corresponding to unmethylated FMR1. Of 24 samples from affected males, 9 (38%) showed 2 melting peaks, suggesting that cellular methylation mosaicism is common in fragile X syndrome. Conclusions: MS-MCA allows rapid and reliable identification of fragile X syndrome in male patients.

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