Mosaicism for the FMR1 gene influences adaptive skills development in fragile X‐affected males

Cohen, Ira L.; Nolin, Sarah L.; Sudhalter, Vicki; Ding, Xiao‐Hua; Dobkin, Carl; Brown, W. Ted

doi:10.1002/(sici)1096-8628(19960809)64:2<365::aid-ajmg26>3.3.co;2-p

Cited by 18 publications

(22 citation statements)

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“…No association was observed between IQ and FMRP in males with a fully methylated full mutation, although it is important to point out that there is little variation in FMRP expression within this group. Although our understanding of the impact of FMRP on the FXS phenotype is still in its infancy, the evidence documenting associations in both the neurocognitive and psychiatric domains of the phenotype highlights the importance of exploring the impact of FMRP expression on the FXS phenotype in both males and females (e.g., Cohen et al, 1996;Menon, Kwon, Eliez, Taylor, & Reiss, 2000;Bailey, Hatton, Skinner, & Mesibov, 2001;Bailey, Hatton, Tassone, Skinner, & Taylor, 2001;Kwon et al, 2001;Loesch et al, 2002;Loesch, Huggins, & Hagerman, 2004).…”

Section: Fxsmentioning

confidence: 99%

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

Thurman

Kover

Brown

et al. 2017

J Speech Lang Hear Res

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a,bPurpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1-4), providing 198 data points for analysis. Results: Participants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed. Conclusions: Noncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills.

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Section: Fxsmentioning

confidence: 99%

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

Thurman

Kover

Brown

et al. 2017

J Speech Lang Hear Res

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“…This pattern is observed in 20-40% of male and 9% of female subjects. 6 Because the premutation alleles undergo normal transcription and translation, 7,8 mosaic males are capable of producing FMR1 protein in some cells. As a result, the behaviour of mosaics, as a group, is less impaired than that of non-mosaic full mutation males.…”

Section: Introductionmentioning

confidence: 99%

Feasibility and acceptance of screening for fragile X mutations in low-risk pregnancies

et al. 1999

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Fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Most women carriers of the fragile X mutation are unaware of their condition. We critically evaluated whether screening pregnant women at low risk for FMR1 mutation would be feasible as a routine part of antenatal care in general practice. We also studied acceptance and attitudes to gene testing. From July 1995 until December 1996, a carrier test was offered at the Kuopio City Health Centre free of charge to all pregnant women in the first trimester following counselling given by midwives on fragile X syndrome. All women found to be carriers of FMR1 gene mutations underwent detailed genetic counselling and were offered prenatal testing. Attitudes towards the gene test were elicited by questionnaire. Most pregnant women (85%) elected to undertake the gene test. Six women were found to be carriers (a rate of 1 in 246), and all subsequently accepted prenatal testing. Three foetuses had a normal FMR1 gene, one had a large premutation, one a 'size mosaic' mutation pattern, and another a full mutation. This observational and interventional study demonstrates that antenatal screening provides an effective way of identifying carriers and incorporating prenatal testing into this process.

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“…This approach can advance investigations that assess the amount and distribution of skewing and mosaicism in various tissues of affected females (Rousseau et al 1991b;Carrel and Willard 1996). Such investigation can help to evaluate to which extent the clinical phenotype in affected women is influenced by such epigenetic modifications (Rousseau et al 1991b;Kolehmainen and Karant 1994;Allingham-Hawkins et al 1996;Cohen et al 1996;Dobkin et al 1996).…”

Section: Methodsmentioning

confidence: 99%

“…Varying degrees of methylation or methylation mosaicism may also influence the severity of the phenotype (Rousseau et al 1991b;Kolehmainen and Karant 1994;Kirchgessner et al 1995;AllinghamHawkins et al 1996;Cohen et al 1996;Dobkin et al 1996;Maddalena et al 1996;Stöger et al 1997;Wöhrle et al 1998). Such situations can be encountered in females with skewed inactivation of either the normal or the abnormal X chromosome or in mosaic males with a combination of full and premutation cell lines (Rousseau et al 1991b;Kolehmainen and Karant 1994;Kirchgessner et al 1995;Allingham-Hawkins et al 1996;Cohen et al 1996;Dobkin et al 1996;Maddalena et al 1996;Stöger et al 1997;Wöhrle et al 1998).…”

Section: Andreas Weinhäusel · Oskar a Haasmentioning

confidence: 99%

“…Nevertheless, at best, only male individuals can be reliably evaluated with these tests. The various combinations of normal, premutation, and full mutation alleles together with the possibility of skewed X-chromosome inactivation and size or methylation mosaicism still pose a diagnostic challenge that has so far been impossible to cover with one simple diagnostic procedure (Brown et al 1993;Rousseau et al 1991b;Kolehmainen and Karant 1994;Kirchgessner et al 1995;Allingham-Hawkins et al 1996;Cohen et al 1996;Dobkin et al 1996;Maddalena et al 1996;Stöger et al 1997;Panagopoulos et al 1999). We therefore present a simple PCR strategy that combines repeat-length and methylation analysis in a cost-and time-efficient fashion.…”

Section: Andreas Weinhäusel · Oskar a Haasmentioning

confidence: 99%

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Evaluation of the fragile X (FRAXA) syndrome with methylation-sensitive PCR

Weinhäusel

Haas

2001

Hum Genet

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The fragile X (FRAXA) syndrome is the most common form of inherited mental retardation in males. Its peculiar pattern of inheritance results from the parent of origin-specific expansion of a CGG-repeat within the FMR1 gene on the X chromosome. In patients, gene function is abolished by hypermethylation of the promoter and the massively expanded repeat. We have developed a methylation-sensitive polymerase chain reaction (MS-PCR) strategy that combines repeat-length and methylation analysis of the CGG-repeat and the promoters of the FMR1 and XIST genes. The allelic methylation of the latter opposes that of the FMR promoter and serves as an internal control and standard for semiquantitative analyses. This system enables the delineation of 11 distinct patterns encountered in nonaffected, carrier, and affected males and females. We have evaluated our system on well-defined samples with different FMR1 mutations and have used it for the diagnostic evaluation of 253 male and 80 female probands. In the male group, we have identified five full mutations, and three gray-zone and premutation alleles with 54, 55, and 62 repeats, respectively. The female group consists of 33 normal homozygote and 41 heterozygote individuals, two of whom harbor a gray-zone allele with 47 repeats, none with a premutation, and six with a full mutation. Our MS-PCR approach allows the currently most comprehensive diagnostic evaluation of the FRAXA syndrome in a cost- and time-efficient fashion. In addition, it is a valuable tool for the analysis of clonality and skewing phenomena in females.

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Mosaicism for the FMR1 gene influences adaptive skills development in fragile X‐affected males

Cited by 18 publications

References 0 publications

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

Feasibility and acceptance of screening for fragile X mutations in low-risk pregnancies

Evaluation of the fragile X (FRAXA) syndrome with methylation-sensitive PCR

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