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

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.

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

PEDIATRICS ◽

10.1542/peds.97.1.122 ◽

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

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Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

Acta Biochimica Polonica ◽

10.18388/abp.1996_4508 ◽

1996 ◽

Vol 43 (2) ◽

pp. 383-388

Author(s):

M Milewski ◽

M Zygulska ◽

J Bal ◽

W H Deelen ◽

E Obersztyn ◽

...

Keyword(s):

Fragile X Syndrome ◽

Dna Sequence ◽

Clinical Features ◽

Fragile Site ◽

Fragile X ◽

Fmr1 Gene ◽

Repeat Number ◽

Full Mutation ◽

Cgg Repeats ◽

Large Expansion

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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A Novel Polymorphism in the FMR1 Gene: Implications for Clinical Testing of Fragile X Syndrome

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-95-anpitf ◽

2008 ◽

Vol 132 (1) ◽

pp. 95-98

Author(s):

Bharat Thyagarajan ◽

Matthew Bower ◽

Michael Berger ◽

Sidney Jones ◽

Michelle Dolan ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Mental Retardation ◽

Fragile X Syndrome ◽

Southern Blot ◽

Trinucleotide Repeat ◽

Fragile X ◽

Fmr1 Gene ◽

Chain Reaction ◽

Cgg Repeat ◽

Polymerase Chain

Abstract Fragile X syndrome is the most common cause of inherited mental retardation among males. In most cases, the molecular basis of fragile X syndrome is the expansion and subsequent methylation of a CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Laboratory diagnosis usually relies on a combination of Southern blot and polymerase chain reaction analyses. In this case report we describe an unusual Southern blot result in a patient who presented with developmental delay and had a normal CGG repeat number by polymerase chain reaction analysis. Further investigation revealed a novel G3310C transversion in the FMR1 gene resulting in a new recognition site for the BssHII restriction enzyme. This novel restriction site could potentially mimic a partial deletion of the FMR1 gene on Southern blot analysis and thus represents a possible pitfall in the diagnosis of fragile X syndrome.

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Mosaicism in Fragile X syndrome: A family case series

Journal of Intellectual Disabilities ◽

10.1177/1744629521995346 ◽

2021 ◽

pp. 174462952199534

Author(s):

Wilmar Saldarriaga ◽

Laura Yuriko González-Teshima ◽

Jose Vicente Forero-Forero ◽

Hiu-Tung Tang ◽

Flora Tassone

Keyword(s):

Mental Retardation ◽

Fragile X Syndrome ◽

Fragile X ◽

Fmr1 Gene ◽

Molecular Testing ◽

Full Mutation ◽

Mild Phenotype ◽

Variable Expression ◽

Fragile X Mental Retardation ◽

Classic Phenotype

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 ( FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

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Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene

Cureus ◽

10.7759/cureus.16340 ◽

2021 ◽

Author(s):

Farzane Vafaeie ◽

Masoome Alerasool ◽

Nasrin Kaseb Mojaver ◽

Majid Mojarrad

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Fmr1 Gene ◽

Full Mutation

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Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells

Genes ◽

10.3390/genes11040356 ◽

2020 ◽

Vol 11 (4) ◽

pp. 356 ◽

Cited By ~ 1

Author(s):

Daman Kumari ◽

Nicholas Sciascia ◽

Karen Usdin

Keyword(s):

Dna Methylation ◽

Fragile X Syndrome ◽

Fragile X ◽

Fmr1 Gene ◽

Mrna Levels ◽

H3k9 Methylation ◽

Methyl Transferase ◽

Cgg Repeat ◽

Heterochromatin Formation ◽

Gene Reactivation

In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the FMR1 gene in FXS patient cells and is thus a potential druggable target. However, its contribution to the silencing process is unclear. Here, we studied the effect of small molecule inhibitors of H3K9 methylation on FMR1 expression in FXS patient cells. Chaetocin showed a small effect on FMR1 gene reactivation and a synergistic effect on FMR1 mRNA levels when used in combination with AZA. Additionally, chaetocin, BIX01294 and 3-Deazaneplanocin A (DZNep) were able to significantly delay the re-silencing of AZA-reactivated FMR1 alleles. These data are consistent with the idea that H3K9 methylation precedes DNA methylation and that removal of DNA methylation is necessary to see the optimal effect of histone methyl-transferase (HMT) inhibitors on FMR1 gene expression. Nonetheless, our data also show that drugs targeting repressive H3K9 methylation marks are able to produce sustained reactivation of the FMR1 gene after a single dose of AZA.

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