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

Yoshimi Inaba, Amy S. Herlihy, Charles E. Schwartz, Cindy Skinner, Quang M. Bui, Joanna Cobb, Elva Z. Shi, David Francis, Alison Arvaj, David J. Amor, Kate Pope, Tiffany Wotton, Jonathan Cohen, Jacqueline K. Hewitt, Randi J Hagerman, Sylvia A. Metcalfe, John L. Hopper, Danuta Z. Loesch, Howard R. Slater, David E. Godler

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Purpose:We show that a novel fragile X-related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening.Methods:Fragile X-related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG <40), 187 premutation (CGG 56-170), and 242 full-mutation (CGG ∼200-2,000) males and females, 106 sex chromosome aneuploidy individuals, and 151 cytogenetically normal controls.Results:At the 0.435 threshold, fragile X-related epigenetic element 2 analysis in males was robust on both blood DNA and newborn blood spots, with specificity and sensitivity of ∼100% for full-mutation genotype. In females, the specificity was 99%, whereas half of full-mutation females were above the 0.435 threshold in both blood DNA and newborn blood spots. Furthermore, at this threshold, the test could not differentiate individuals with Klinefelter syndrome from female controls without using the SRY marker. When combined with SRY analysis, the test was consistent with most results for sex chromosome aneuploidies from karyotyping.Conclusion: Setting specific thresholds for fragile X-related epigenetic element 2 analysis and including the SRY marker provides the option to either include or exclude detection of sex chromosome aneuploidies as part of fragile X syndrome newborn screening.

Original languageEnglish (US)
Pages (from-to)290-298
Number of pages9
JournalGenetics in Medicine
Volume15
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Fragile X Syndrome
Sex Chromosomes
Validation Studies
X Chromosome
Aneuploidy
Methylation
Epigenomics
Mutation
DNA
Klinefelter Syndrome
Karyotyping
Saliva
Genotype
Sensitivity and Specificity

Keywords

  • FMR1
  • fragile X syndrome
  • intron
  • methylation
  • newborn screening
  • sex chromosome aneuploidy

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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, Yoshimi; Herlihy, Amy S.; Schwartz, Charles E.; Skinner, Cindy; Bui, Quang M.; Cobb, Joanna; Shi, Elva Z.; Francis, David; Arvaj, Alison; Amor, David J.; Pope, Kate; Wotton, Tiffany; Cohen, Jonathan; Hewitt, Jacqueline K.; Hagerman, Randi J; Metcalfe, Sylvia A.; Hopper, John L.; Loesch, Danuta Z.; Slater, Howard R.; Godler, David E.

In: Genetics in Medicine, Vol. 15, No. 4, 04.2013, p. 290-298.

Research output: Contribution to journalArticle

Inaba, Y, Herlihy, AS, Schwartz, CE, Skinner, C, Bui, QM, Cobb, J, Shi, EZ, Francis, D, Arvaj, A, Amor, DJ, Pope, K, Wotton, T, Cohen, J, Hewitt, JK, Hagerman, RJ, Metcalfe, SA, Hopper, JL, Loesch, DZ, Slater, HR & Godler, DE 2013, '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', Genetics in Medicine, vol. 15, no. 4, pp. 290-298. https://doi.org/10.1038/gim.2012.134
Inaba, Yoshimi ; Herlihy, Amy S. ; Schwartz, Charles E. ; Skinner, Cindy ; Bui, Quang M. ; Cobb, Joanna ; Shi, Elva Z. ; Francis, David ; Arvaj, Alison ; Amor, David J. ; Pope, Kate ; Wotton, Tiffany ; Cohen, Jonathan ; Hewitt, Jacqueline K. ; Hagerman, Randi J ; Metcalfe, Sylvia A. ; Hopper, John L. ; Loesch, Danuta Z. ; Slater, Howard R. ; Godler, David E. / 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. In: Genetics in Medicine. 2013 ; Vol. 15, No. 4. pp. 290-298.
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abstract = "Purpose:We show that a novel fragile X-related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening.Methods:Fragile X-related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG <40), 187 premutation (CGG 56-170), and 242 full-mutation (CGG ∼200-2,000) males and females, 106 sex chromosome aneuploidy individuals, and 151 cytogenetically normal controls.Results:At the 0.435 threshold, fragile X-related epigenetic element 2 analysis in males was robust on both blood DNA and newborn blood spots, with specificity and sensitivity of ∼100{\%} for full-mutation genotype. In females, the specificity was 99{\%}, whereas half of full-mutation females were above the 0.435 threshold in both blood DNA and newborn blood spots. Furthermore, at this threshold, the test could not differentiate individuals with Klinefelter syndrome from female controls without using the SRY marker. When combined with SRY analysis, the test was consistent with most results for sex chromosome aneuploidies from karyotyping.Conclusion: Setting specific thresholds for fragile X-related epigenetic element 2 analysis and including the SRY marker provides the option to either include or exclude detection of sex chromosome aneuploidies as part of fragile X syndrome newborn screening.",
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T1 - 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

T2 - A technical validation study

AU - Inaba, Yoshimi

AU - Herlihy, Amy S.

AU - Schwartz, Charles E.

AU - Skinner, Cindy

AU - Bui, Quang M.

AU - Cobb, Joanna

AU - Shi, Elva Z.

AU - Francis, David

AU - Arvaj, Alison

AU - Amor, David J.

AU - Pope, Kate

AU - Wotton, Tiffany

AU - Cohen, Jonathan

AU - Hewitt, Jacqueline K.

AU - Hagerman, Randi J

AU - Metcalfe, Sylvia A.

AU - Hopper, John L.

AU - Loesch, Danuta Z.

AU - Slater, Howard R.

AU - Godler, David E.

PY - 2013/4

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N2 - Purpose:We show that a novel fragile X-related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening.Methods:Fragile X-related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG <40), 187 premutation (CGG 56-170), and 242 full-mutation (CGG ∼200-2,000) males and females, 106 sex chromosome aneuploidy individuals, and 151 cytogenetically normal controls.Results:At the 0.435 threshold, fragile X-related epigenetic element 2 analysis in males was robust on both blood DNA and newborn blood spots, with specificity and sensitivity of ∼100% for full-mutation genotype. In females, the specificity was 99%, whereas half of full-mutation females were above the 0.435 threshold in both blood DNA and newborn blood spots. Furthermore, at this threshold, the test could not differentiate individuals with Klinefelter syndrome from female controls without using the SRY marker. When combined with SRY analysis, the test was consistent with most results for sex chromosome aneuploidies from karyotyping.Conclusion: Setting specific thresholds for fragile X-related epigenetic element 2 analysis and including the SRY marker provides the option to either include or exclude detection of sex chromosome aneuploidies as part of fragile X syndrome newborn screening.

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KW - FMR1

KW - fragile X syndrome

KW - intron

KW - methylation

KW - newborn screening

KW - sex chromosome aneuploidy

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