Fragile X Mental Retardation 1 (FMR1) Intron 1 Methylation in Blood Predicts Verbal Cognitive Impairment in Female Carriers of Expanded FMR1 Alleles: Evidence from a Pilot Study

Godler, David E.; Slater, Howard R.; Bui, Minh; Storey, Elsdon; Ono, Michele Y.; Gehling, Freya; Inaba, Yoshimi; Francis, David; Hopper, John L.; Kinsella, Glynda; Amor, David J.; Hagerman, Randi J.; Loesch, Danuta Z.

doi:10.1373/clinchem.2011.177626

Cited by 37 publications

(60 citation statements)

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“…13 In Figure 2, we show that in a larger cohort, the 0.435 methylation threshold can separate FM individuals from PM and control groups as effectively in 500 ng of DNA from venous blood as in cell extract from one 3-mm punch per sample from dried blood spots of adults and newborns. …”

Section: Discussionmentioning

confidence: 90%

“…We found that by including the Y chromosome marker with a 0.435 MOR FXS methylation threshold, 13 almost all sex chromosome aneuploidies could be differentiated with sensitivity and specificity approaching 100%. The exceptions were one 49,XXXXY and two 47,XXX individuals who could not be differentiated from control females.…”

Section: Using the Free2 Methylation Test For Combined Fxs And Sex Chmentioning

confidence: 88%

“…30 Another important advance has been the development of a suitable test 1,13,31 with high sensitivity and specificity for epimutation detection and prognosis in affected individuals. Of note, this test does not detect the very common unmethylated, grayzone, and PM alleles that are associated with currently untreatable, late-onset disorders.…”

Section: Genetics In Medicine | Volume 15 | Number 4 | April 2013mentioning

confidence: 99%

“…[10][11][12][13] This test also has the potential to be used for detection of sex chromosome aneuploidy.…”

mentioning

confidence: 99%

“…22,23 The FREE2 blood test identifies cognitively impaired FM males and females with specificity and sensitivity approaching 100%, but cannot distinguish between small-expansion carriers and healthy controls or high-functioning males with unmethylated FM alleles. [11][12][13] This is highly advantageous for newborn, infant, or early childhood population screening because the test potentially detects only those who would directly benefit from early diagnosis. 24 In this study, we performed technical validation for the FREE2 analysis in detection of FXS alleles in archival newborn and adult dried blood spots and venous blood DNA.…”

mentioning

confidence: 99%

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Fragile X–related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study

Inaba

Herlihy

Schwartz

et al. 2013

Genetics in Medicine

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Section: Discussionmentioning

confidence: 90%

Section: Using the Free2 Methylation Test For Combined Fxs And Sex Chmentioning

confidence: 88%

Section: Genetics In Medicine | Volume 15 | Number 4 | April 2013mentioning

confidence: 99%

“…[10][11][12][13] This test also has the potential to be used for detection of sex chromosome aneuploidy.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Fragile X–related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study

Inaba

Herlihy

Schwartz

et al. 2013

Genetics in Medicine

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Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction

Stark

Francis

Gaffney

et al. 2015

American J of Med Genetics Pt A

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Fragile X syndrome is the most common single gene cause of intellectual disability in boys. It is usually caused by expansion of a CGG repeat sequence in the 5 0 untranslated region, which is associated with methylation and silencing of the FMR1 promoter and adjacent regions. A repeat size of less than 45 is considered normal, 45-54 repeats are termed "gray zone" (GZ) or intermediate alleles, and 55-200 are considered premutation (PM). These allele types are unmethylated. In contrast, alleles with more than 200 repeats, termed full mutations (FM), are methylated [Maddalena et al., 2001]. PM and FM alleles are unstable and usually expand when maternally transmitted. Figures regarding the risk of expansion based on the size of the maternal allele are available and widely used in counseling couples requesting prenatal diagnosis in pregnancies at risk of the condition [Jin and Warren, 2000;Nolin et al., 2003]. Conventionally, prenatal testing involves fetal sex determination by FISH, followed by sizing of the FMR1 allele either through Southern blot or long-range PCR. More recently, methylation testing of Fragile X Related Epigenetic Elements (FREE) located on the 5 0 and 3 0 ends of the FMR1 promoter, has started to be used particularly in the postnatal setting to accurately measure the fraction of methylated alleles [Godler et al., 2010;Godler et al., 2012]. Methylation testing for allele sizes between 150 and 250 CGG repeats is particularly important, because the technical error typically associated with Southern blot CGG sizing in this range is AE30-50 CGG repeats [Zhou et al., 2004]. High levels of methylation of the FREE biomarkers are negatively correlated with verbal cognitive abilities and FMR1 protein expression (FMRP), the latter essential for normal neurodevelopment [Godler et al., 2010;Godler et al., 2012].We present a case where prenatal diagnosis for fragile X syndrome in a male fetus was complicated by transmission of a smaller CGG repeat expansion, that is, a FM retraction. The proband in this family is a FM female carrier with 29 and 390-907 CGG repeats. She has completed secondary education, is in full-time employment, and does not have learning difficulties. She has two male cousins with fragile X syndrome who were severely affected, and a female cousin with FM with mild learning difficulties. She requested prenatal diagnosis and underwent chorionic villus sampling (CVS) at 12 weeks gestation. Male sex of the fetus was determined using X and Y-specific FISH probes. Southern blot testing of uncultured chorionic villi DNA (trophoblast and mesenchymal cells) showed a fragile X allele in the PM range (155 repeats; Fig. 1A). Subsequent Southern blot on cultured CVS DNA (mesenchymal cells) showed only a FM smear (320-730 repeats; Fig. 1B). Given the discordant results, amniocentesis was performed and Southern blot testing of amniotic fluid (AF) DNA showed a mosaic PM (180 repeats)/FM (257-923 repeats) result (Fig. 1C). Testing of a cheek brush sample from the mother confirmed 29 and 390-907 CGG repeats ...

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Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report

Hwang

Aliaga

Arpone

et al. 2016

American J of Med Genetics Pt A

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CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing. © 2016 Wiley Periodicals, Inc.

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Fragile X Mental Retardation 1 (FMR1) Intron 1 Methylation in Blood Predicts Verbal Cognitive Impairment in Female Carriers of Expanded FMR1 Alleles: Evidence from a Pilot Study

Cited by 37 publications

References 37 publications

Fragile X–related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study

Fragile X–related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study

Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction

Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report

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