Extra Alleles in FMR1 Triple-Primed PCR

Wakeling, Erin; Al‐Nahhas, Adil; Feldman, Gerald L.

doi:10.1016/j.jmoldx.2014.06.006

Cited by 4 publications

(7 citation statements)

References 40 publications

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“…While somatic instability of premutation and full mutation alleles is well documented ( Cambouris et al, 1996 ; Dobkin et al, 1996 ; Mingroni-Netto et al, 1996 ), information regarding unstable normal alleles ( Sullivan et al, 2005 ; Nolin et al, 2011 ) is limited. In contrast to the report of Wakeling et al (2014) , Maia et al (2017) reported on four FXS mosaic males carrying normal, premutated and full mutation FMR1 alleles. The authors suggested that the normal allele of these patients resulted from postzygotic contraction of the full expansion.…”

Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 58%

“… Sharony et al (2012) , Wakeling et al (2014) , and also our laboratory (data not shown) experienced instability/mosaicism in the normal–intermediate range (less than 55 CGG repeats). Wakeling et al (2014) reported that about 0.4% of the normal population tested showed an extra allele. Our experience from the routine FMR1 screening test of normal population as well as the Sharony et al (2012) study showed a lower frequency of cases with an extra allele (12 out of 13,000 cases; data not shown) in the normal range size.…”

Section: Discussionmentioning

confidence: 58%

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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: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 58%

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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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“…In addition, if these two cases have small population sizes of mosaicism, it can be detected by TP-PCR but not by FA. These results are similar to previously reported cases demonstrating different results for FA and TP-PCR, which were attributed to different DNA amounts [ 14 ].…”

Section: Discussionsupporting

confidence: 92%

Accuracy and Performance Evaluation of Triplet Repeat Primed PCR as an Alternative to Conventional Diagnostic Methods for Fragile X Syndrome

Kim

Yang

et al. 2021

Ann Lab Med

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Background Conventional diagnosis of fragile X syndrome (FXS) is based on a combination of fragment analysis (FA) and Southern blotting (SB); however, this diagnostic approach is time- and labor-intensive and has pitfalls such as the possibility of missing large number alleles. Triplet repeat primed PCR (TP-PCR) is a current alternative used to overcome these limitations. We evaluated the diagnostic usefulness of TP-PCR compared with the conventional diagnostic protocol consisting of FA and/or SB in terms of allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers. Methods From November 2013 to March 2018, 458 patients (326 males, 132 females) were simultaneously examined using FA and/or SB and TP-PCR by detecting CGG repeat numbers in FMR1 gene and diagnosed as per American College of Medical Genetics guidelines. Results The TP-PCR results showed high concordance with the FA and/or SB results for all three aspects (allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers). TP-PCR detected CGG expansions ≥200 in all full mutation (FM) allele cases in male patients, as well as both the normal allele (NL) and FM allele in female carriers. In premutation (PM) allele carriers, the TP-PCR results were consistent with the FA and/or SB results. In terms of zygosity concordance in female genetic carriers, 12 NL cases detected by TP-PCR showed a merged peak consisting of two close heterozygous peaks; however, this issue was resolved using a 10-fold dilution. Conclusions TP-PCR may serve as a reliable alternative method for FXS diagnosis.

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“…First, allele expansion occurs mainly during maternal but not paternal transmission, regardless AGG loss or CGG repeat length. Second, although FMR1 allelic mosaicism is generally characterized by the presence of a premutation and a full mutation alelle, it has been reported also within the normal CGG repeat range (3 alleles of different sizes) regardless AGG loss (Sharony et al, ; Wakeling, Nahhas, & Feldman, ). Indeed, in this study we report cases with AGG loss in both alleles in the normal CGG repeat length which appears to be in contrast with the expectation that the loss of AGG interruptions causing CGG repeat instability.…”

Section: Introductionmentioning

confidence: 99%

The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity

Manor

Gonen

Sarussi

et al. 2019

Molec Gen & Gen Med

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BackgroundThe prevalence and the role of AGG interruptions within the FMR1 gene in the normal population is unknown. In this study, we investigated the frequent of AGG loss, in one or two alleles within the normal population. The role of AGG in the FMR1 stability has been assessed by correlating AGG loss to the prevalence of premutation/full mutation in two ethnic groups differing in their consanguinity rate: high versus low consanguinity rate (HCR vs. LCR).MethodsThe CGG repeat allele size and AGG presence were measured in 6,865 and 6,204 females belonging to the LCR (5%) and HCR (>45%) groups, respectively, by Tripled‐Primed‐PCR technique.ResultsA lower prevalence of the premutation was observed in the HCR (1:158) as compared to the LCR group (1:128). No full mutation was found in the HCR females while in the LCR group the prevalence found was 1:1,149. Homozygosity rate was higher in the HCR population compared to the LCR group.The overall AGG loss was higher in the HCR population than in the LCR and increased with increased CGG repeat number in both ethnic groups.ConclusionsAlthough we observed a significantly higher rate of homozygosity and AGG loss in the HCR group, this did not affect the prevalence of the premutation and full mutation in this population. Their prevalence was significantly lower than in the LCR population. Finally, we discuss whether the loss of AGG could be also a polymorphic event but not only a stabilizing factor.

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Extra Alleles in FMR1 Triple-Primed PCR

Cited by 4 publications

References 40 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?

Accuracy and Performance Evaluation of Triplet Repeat Primed PCR as an Alternative to Conventional Diagnostic Methods for Fragile X Syndrome

The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity

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