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

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

Genes ◽

10.3390/genes11030248 ◽

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.

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

Journal of Medical Genetics ◽

10.1136/jmg.33.4.338 ◽

1996 ◽

Vol 33 (4) ◽

pp. 338-340 ◽

Cited By ~ 29

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

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Faculty Opinions recommendation of Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732704934.793544461 ◽

2018 ◽

Author(s):

Laurent Villard

Keyword(s):

Dna Methylation ◽

Fragile X Syndrome ◽

Fragile X ◽

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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Roles of ZF5 and CGGBP-20 transcription factors in regulating expression of human FMR1 gene responsible for fragile X-syndrome

Cell and Tissue Biology ◽

10.1134/s1990519x10010050 ◽

2010 ◽

Vol 4 (1) ◽

pp. 54-62 ◽

Cited By ~ 1

Author(s):

P. V. Gulyy ◽

S. V. Orlov ◽

E. B. Dizhe ◽

K. B. Kuteikin-Teplyakov ◽

I. A. Ignatovich ◽

...

Keyword(s):

Transcription Factors ◽

Fragile X Syndrome ◽

Fragile X ◽

Fmr1 Gene

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Fragile X: A Family of Disorders

Cognitive and Behavioral Abnormalities of Pediatric Diseases ◽

10.1093/oso/9780195342680.003.0024 ◽

2010 ◽

Author(s):

Ann M. Mastergeorge ◽

Jacky Au

Keyword(s):

Intellectual Disability ◽

Fragile X Syndrome ◽

X Chromosome ◽

Culture Media ◽

Fragile Site ◽

Fragile X ◽

Single Gene ◽

Repeat Sequence ◽

Full Mutation ◽

Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

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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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Urine-Derived Epithelial Cell Lines: A New Tool to Model Fragile X Syndrome (FXS)

Cells ◽

10.3390/cells9102240 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2240

Author(s):

Marwa Zafarullah ◽

Mittal Jasoliya ◽

Flora Tassone

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Fragile X Syndrome ◽

Cell Lines ◽

Behavioral Problems ◽

Cell Model ◽

Fragile X ◽

Healthy Controls ◽

Full Mutation ◽

Epithelial Cell Lines

Fragile X syndrome (FXS) is an X-linked neurodevelopmental condition associated with intellectual disability and behavioral problems due to the lack of the Fragile X mental retardation protein (FMRP), which plays a crucial role in synaptic plasticity and memory. A desirable in vitro cell model to study FXS would be one that can be generated by simple isolation and culture method from a collection of a non-invasive donor specimen. Currently, the various donor-specific cells can be isolated mainly from peripheral blood and skin biopsy. However, they are somewhat invasive methods for establishing cell lines from the primary subject material. In this study, we characterized a cost-effective and straightforward method to derive epithelial cell lines from urine samples collected from participants with FXS and healthy controls (TD). The urine-derived cells expressed epithelial cell surface markers via fluorescence-activated cell sorting (FACS). We observed inter, and the intra-tissue CGG mosaicism in the PBMCs and the urine-derived cells from participants with FXS potentially related to the observed variations in the phenotypic and clinical presentation FXS. We characterized these urine-derived epithelial cells for FMR1 mRNA and FMRP expression and observed some expression in the lines derived from full mutation mosaic participants. Further, FMRP expression was localized in the cytoplasm of the urine-derived epithelial cells of healthy controls. Deficient FMRP expression was also observed in mosaic males, while, as expected, no expression was observed in cells derived from participants with a hypermethylated full mutation.

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