Advanced technologies for the molecular diagnosis of fragile X syndrome

Tassone, Flora

doi:10.1586/14737159.2015.1101348

Cited by 33 publications

(27 citation statements)

References 92 publications

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“…All samples showed presence of only the 19 CGG repeat allele as observed in DNA isolated from the amniotic fluid but without the less abundant peak corresponding to the 29 CGG repeat allele. The less abundant peak observed from DNA isolated from amniotic fluid points to low level of mother contamination, which can been detected by the Amplidex PCR (Asuragen) as it has been proven to be much more sensitive than other techniques ( Filipovic-Sadic et al, 2010 ; Tassone, 2015 ). None of the samples tested showed evidence of an expanded allele excluding the possibility of mosaicism.…”

Section: Resultsmentioning

confidence: 99%

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

et al. 2017

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Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range.

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Section: Resultsmentioning

confidence: 99%

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

et al. 2017

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“…This PCR provides information about the exact CGG number, AGG interruptions, and discriminates between normal, intermediate, premutation and full mutation alleles as well as homozygous females from women with an allele in the normal range and another allele in the premutation or full mutation range. 26 A methylation-specific PCR, TP-MS-PCR, has been developed, and this technique is able to evaluate the methylation status, being even more sensitive than Southern blot analysis. 27 Currently the best method for routine prenatal and postnatal diagnosis consists in a combination of TP-PCR and TP-MS-PCR using DNA extracted from any tissue.…”

Section: Diagnosis Of Fxsmentioning

confidence: 99%

Fragile X syndrome: An overview and update of the FMR1 gene

et al. 2017

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Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene. tions. In 1999, the study of fragile X pedigrees revealed a higher incidence of primary ovarian insufficiency related to the FMR1 gene, and this condition was named premature ovarian failure (POF) and then later fragile X premature ovarian insufficiency (FXPOI). 6 This term encompasses a continuum of severity in ovarian dysfunction ranging from normal menses and normal hormonal levels, although reduced fertility, to the most severe form of this condition in which folliclestimulating hormone is elevated, menses are abnormal or absent, and fertility is drastically reduced. 7 After further studies, Hagerman et al described a neurological disease related to the FMR1 premutation that was named fragile X-associated tremor/ataxia syndrome (FXTAS). 8 Finally, since 2007 the spectrum of the clinical phenotype associated with the FMR1 premutation has continuously widened. This review is an update of the diseases associated with the FMR1 gene.2 | FRAGILE X SYNDROME FXS (#MIM300624; ORPHA 908) is the most common cause of inherited ID (1%-2% of all ID) and the leading form of the monogenic cause of autism and autism spectrum disorders (ASD) (Figure 1). The

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“…IM alleles also share the molecular characteristics of PM expansions; elevated FMR1 mRNA and reduction in FMRP levels have been noted [44,86]. IM allele frequency in the general population varies between 1 in 22 to 66 females and 1 in 42 to 112 males [87]. …”

Section: Potential Risks and Instability Of Intermediate-sized Allmentioning

confidence: 99%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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Advanced technologies for the molecular diagnosis of fragile X syndrome

Cited by 33 publications

References 92 publications

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Fragile X syndrome: An overview and update of the FMR1 gene

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

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