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

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

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Cognitive status in females with mutations in the FMR1 (fragile Xmental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS: Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55-200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ<70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS: A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10 -5) after adjustment for multiple measures. CONCLUSIONS: The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment inFMfemales, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

Original languageEnglish (US)
Pages (from-to)590-598
Number of pages9
JournalClinical Chemistry
Volume58
Issue number3
DOIs
StatePublished - Mar 2012

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Methylation
Intellectual Disability
Introns
Blood
Alleles
Fragile X Mental Retardation Protein
Biomarkers
Fragile X Syndrome
Exons
Screening
Hematologic Tests
Southern Blotting
Genes
Chemical activation
Epigenomics
Newborn Infant
Sensitivity and Specificity
Mutation
Cognitive Dysfunction
Population

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

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, Quang M.; 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.

In: Clinical Chemistry, Vol. 58, No. 3, 03.2012, p. 590-598.

Research output: Contribution to journalArticle

Godler, DE, Slater, HR, Bui, QM, Storey, E, Ono, MY, Gehling, F, Inaba, Y, Francis, D, Hopper, JL, Kinsella, G, Amor, DJ, Hagerman, RJ & Loesch, DZ 2012, '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', Clinical Chemistry, vol. 58, no. 3, pp. 590-598. https://doi.org/10.1373/clinchem.2011.177626
Godler, David E. ; Slater, Howard R. ; Bui, Quang M. ; 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. / 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. In: Clinical Chemistry. 2012 ; Vol. 58, No. 3. pp. 590-598.
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abstract = "BACKGROUND: Cognitive status in females with mutations in the FMR1 (fragile Xmental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS: Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55-200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ<70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS: A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100{\%}) and specificity (98{\%}) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10 -5) after adjustment for multiple measures. CONCLUSIONS: The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment inFMfemales, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.",
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T1 - Fragile X mental retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleles

T2 - Evidence from a pilot study

AU - Godler, David E.

AU - Slater, Howard R.

AU - Bui, Quang M.

AU - Storey, Elsdon

AU - Ono, Michele Y.

AU - Gehling, Freya

AU - Inaba, Yoshimi

AU - Francis, David

AU - Hopper, John L.

AU - Kinsella, Glynda

AU - Amor, David J.

AU - Hagerman, Randi J

AU - Loesch, Danuta Z.

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N2 - BACKGROUND: Cognitive status in females with mutations in the FMR1 (fragile Xmental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS: Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55-200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ<70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS: A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10 -5) after adjustment for multiple measures. CONCLUSIONS: The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment inFMfemales, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

AB - BACKGROUND: Cognitive status in females with mutations in the FMR1 (fragile Xmental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS: Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55-200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ<70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS: A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10 -5) after adjustment for multiple measures. CONCLUSIONS: The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment inFMfemales, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

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