ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics

Monaghan, Kristin G.; Lyon, Elaine; Spector, Elaine

doi:10.1038/gim.2013.61

Cited by 129 publications

(144 citation statements)

References 94 publications

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“…Some studies have shown, however, that reproductive function may be significantly impacted in this range [36]; however, other studies have shown no obvious impact [22,58]. The American College of Obstetrics and Gynecology Genetics Committee, and the American College of Medical Genetics (ACMG), explicitly state that an FMR1 CGG repeat length of <45 'is not associated with an abnormal phenotype' [66]. This 'normal' range, however, may not in fact be a homogenous population.…”

Section: The Cgg Mutationsmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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Section: The Cgg Mutationsmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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“…21 Polymerase chain reaction (PCR)-based analysis was performed in all participants. PCR was performed using an untagged forward primer and a fluorescence-tagged reverse primer, as previously described.…”

Section: Cgg Repeat Analysesmentioning

confidence: 99%

Ethnic effect on FMR1 carrier rate and AGG repeat interruptions among Ashkenazi women

Weiss

Orr-Urtreger

Ber

et al. 2014

Genetics in Medicine

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introductionFragile X syndrome (FXS; OMIM 300624) is the most common form of inherited mental impairment, with a prevalence of approximately 1/4,500 in males. The syndrome is characterized by moderate intellectual disability and behavioral abnormalities, including autistic-like behavior.1,2 The vast majority of FXS cases are caused by an expansion of CGG nucleic-base repeats in the Fragile X mental retardation gene (FMR1). Normal individuals usually have ~30 CGG repeats. An expansion to greater than 200 repeats is associated with abnormal methylation and suppression of FMR1 transcription, causing the absence of the gene product, the FMR protein. 3 The lack of FMR protein, an RNA-binding protein, is responsible for the syndrome. 4 There are four allelic forms of the FMR1 gene with respect to the repeat length. The normal allele form has approximately 5-44 CGG repeats and it is stable on transmission. In these normal alleles, the CGG repeat region is usually interrupted by AGG triplets after every 9 or 10 CGG repeats. These AGG interruptions are believed to maintain repeat integrity by preventing DNA slippage during replication, therefore increasing the repeats' stability.5 The full-mutation allele form has more than 200 repeats, with several hundred to several thousand repeats being typical. In between those two forms fall the intermediate allele form and the premutation allele form. The intermediate allele form falls between the normal and premutation size ranges (45-54 repeats). A proportion of these alleles are unstable and may expand by a few repeats during meiosis. In this range, expansion to the full-mutation allele may occur over two or more generations but not in a single transmission. 6 The premutation allele form is about 55-200 repeats long. It is unstable and commonly expands during transmission. Individuals with the premutations are defined as carriers of the disease. Expansion of an abnormal allele usually occurs when it is transmitted from the mother but not from the father. 7 However, although alleles of 55-59 repeats are defined as premutations, only a very few cases of expansion to a full mutation have actually been reported, emphasizing the fact that such allele sizes are generally stable. 8In general, the risk of expansion of a premutation to a full mutation upon transmission to the offspring is associated with three factors. First, it correlates with the number of CGG repeats.9 Second, the number of AGG interruptions also affects stability on transmission, such that alleles with a high number of CGG repeats that lack AGG interruptions are more prone to expansion. 5,10 A third factor affecting risk of transmission is the genetic background because some haplotypes are associated with an increased instability as compared with others. Purpose: Fragile X syndrome, a common cause of intellectual disability, is usually caused by CGG trinucleotide expansion in the FMR1 gene. CGG repeat size correlates with expansion risk. Premutation alleles (55-200 repeats) may expand to full mutations in female mei...

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“…In addition, in contrast to lymphocytes and amniocytes, the FMR1 gene is not methylated on the inactive X chromosome in the chorionic villi of female fetuses (13).…”

Section: Diagnosis Of Fxsmentioning

confidence: 99%

“…Currently, as the best practice to determine full mutation, laboratories have to use both PCR and Southern blot analysis. Consequently, in their most updated policy statement, the American College of Medical Genetics and Genomics (ACMG) recommends that Southern blot analysis always be performed along with traditional PCR (13). It is worth noting that since the current DNA analyses only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1 have to undergo sequencing of the FMR1 gene in order to be properly diagnosed.…”

Section: Management Of Fxsmentioning

confidence: 99%

Fragile X syndrome as a rare disease in China – Therapeutic challenges and opportunities

Jin

Chen

2015

IRDR

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ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics

Cited by 129 publications

References 94 publications

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Ethnic effect on FMR1 carrier rate and AGG repeat interruptions among Ashkenazi women

Fragile X syndrome as a rare disease in China – Therapeutic challenges and opportunities

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