Testing for Fragile X Gene Mutations Throughout the Life Span

Hagerman, Randi J.; Hagerman, Paul J.

doi:10.1001/jama.2008.684

Cited by 33 publications

(17 citation statements)

References 15 publications

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“…The fragile X or FMR1 DNA test should be considered in individuals at high risk of having fragile X mutations particularly in children with ASD, developmental and intellectual disabilities, women with early menopause, or older adults with intention tremor or ataxia 63. This family tree is unusual because there is only premutation and gray zone involvement.…”

Section: Discussionmentioning

confidence: 99%

Broad Clinical Involvement in a Family Affected by the Fragile X Premutation

Chonchaiya

Utari

Pereira

et al. 2009

Journal of Developmental &Amp; Behavioral Pediatrics

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The mutations in the FMR1 gene have been described as a family of disorders called fragile X-associated disorders (FXD) including fragile X syndrome (FXS), fragile X-associated tremor/ ataxia syndrome (FXTAS), primary ovarian insufficiency and other problems associated with the premutation, such as hypothyroidism, hypertension, neuropathy, anxiety, depression, attention deficit hyperactivity disorders and autism spectrum disorders. The premutation is relatively common in the general population affecting 1 of 130–250 female individuals and 1 of 250–800 male individuals. Therefore, to provide appropriate treatment and genetic counseling for all of the carriers and affected individuals in a family, a detailed family history that reviews many of the disorders that are related to both the premutation and the full mutation should be carried out as exemplified in these cases. To facilitate the integration of this knowledge into clinical practice, this is the first case report that demonstrates only premutation involvement across 3 generations.

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Section: Discussionmentioning

confidence: 99%

Broad Clinical Involvement in a Family Affected by the Fragile X Premutation

Chonchaiya

Utari

Pereira

et al. 2009

Journal of Developmental &Amp; Behavioral Pediatrics

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“…With regard to ovarian reserve, Gleicher et al (17) indicated that the normal range of CGG repeats is 26-34 with a median of 30 (18,20), which encompasses the distribution peaks described herein and by Chen et al (21). These findings suggest that the range of CGG repeats associated with ovarian reserve differs from that associated with neuro/psychiatric risk (22,23) and that a repeat number of >30 is associated with decreased ovarian reserve.The number of CGG repeats in Asians has a characteristic secondary peak of 34-36 repeats in addition to the most frequent peak of 29 to 30 (9). Studies have indicated numbers of <40 CGG repeats in normal Japanese populations, with a minor population showing a peak at 36 repeats in addition to peaks at 29 and 30 repeats (24, 25).…”

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confidence: 85%

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confidence: 85%

Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency

Ishizuka

Okamoto

Hamada

et al. 2011

Fertility and Sterility

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“…Expansions in the triplet repeat region to greater than 200 repeats are associated with hypermethylation of the FMR1 gene and the loss of FMR1 protein production, leading to the fragile X phenotype. This phenotype can include mental retardation, autism, and emotional and psychiatric challenges 5 . The severity of cognitive disability in FXS patients is not associated with the magnitude of the full mutation allele 6 but does vary with methylation status 7, 8 .…”

Section: Introductionmentioning

confidence: 99%

High-resolution methylation polymerase chain reaction for fragile X analysis: Evidence for novel FMR1 methylation patterns undetected in Southern blot analyses

Chen

Hadd

Sah

et al. 2011

Genetics in Medicine

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PURPOSE Fragile X syndrome is associated with the expansion of CGG trinucleotide repeats and subsequent methylation of the fragile X mental retardation-1 (FMR1) gene. Molecular diagnosis of fragile X currently requires Southern blot analysis to assess methylation. This study describes the evaluation of a PCR-only workflow for the determination of methylation status across a broad range of FMR1 genotypes in male and female specimens. METHODS We evaluated a novel method that combines allele-specific methylation PCR and capillary electrophoresis with 8 cell line and 80 clinical samples, including 39 full mutations. Methylation status was determined using a 3-step workflow: 1) differential treatment of genomic DNA using a methylation-sensitive restriction enzyme; 2) PCR with 2 sets of dye-tagged primers; and 3) amplicon sizing by capillary electrophoresis. All samples were analyzed by both methylation PCR and Southern blot analysis. RESULTS FMR1 methylation status and CGG repeat sizing were accurately and reproducibly determined in a set of methylation controls, and genomic DNA samples representing a spectrum of CGG repeat lengths and methylation states. Moreover, methylation PCR revealed allele-specific methylation patterns in premutation alleles that were unobtainable using Southern blot analysis. CONCLUSIONS Methylation PCR enabled high throughput, high resolution, and semi-quantitative methylation assessments of FMR1 alleles, as well as determinations of CGG repeat length. Results for all samples were concordant with corresponding Southern blot analyses. As a result, this study presents a PCR-based method for comprehensive FMR1 analysis. In addition, the identification of novel methylation mosaic patterns revealed after PCR and capillary electrophoresis may be relevant to several FMR1 disorders.

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Testing for Fragile X Gene Mutations Throughout the Life Span

Cited by 33 publications

References 15 publications

Broad Clinical Involvement in a Family Affected by the Fragile X Premutation

Broad Clinical Involvement in a Family Affected by the Fragile X Premutation

Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency

High-resolution methylation polymerase chain reaction for fragile X analysis: Evidence for novel FMR1 methylation patterns undetected in Southern blot analyses

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