Incidence of Fragile X Syndrome by Newborn Screening for Methylated FMR1 DNA
Open accessAbstract
Fragile X syndrome (FXS) results from a CGG-repeat expansion that triggers hypermethylation and silencing of the FMR1 gene. FXS is referred to as the most common form of inherited intellectual disability, yet its true incidence has never been measured directly by large population screening. Here, we developed an inexpensive and high-throughput assay to quantitatively assess FMR1 methylation in DNA isolated from the dried blood spots of 36,124 deidentified newborn males. This assay displays 100% specificity and 100% sensitivity for detecting FMR1 methylation, successfully distinguishing normal males from males with full-mutation FXS. Furthermore, the assay can detect excess FMR1 methylation in 82% of females with full mutations, although the methylation did not correlate with intellectual disability. With amelogenin PCR used for detecting the presence of a Y chromosome, this assay can also detect males with Klinefelter syndrome (KS) (47, XXY). We identified 64 males with FMR1 methylation and, after confirmatory testing, found seven to have full-mutation FXS and 57 to have KS. Because the precise incidence of KS is known, we used our observed KS incidence as a sentinel to assess ascertainment quality and showed that our KS incidence of 1 in 633 newborn males was not significantly different from the literature incidence of 1 in 576 (p = 0.79). The seven FXS males revealed an FXS incidence in males of 1 in 5161 (95% confidence interval of 1 in 10,653-1 in 2500), consistent with some earlier indirect estimates. Given the trials now underway for possible FXS treatments, this method could be used in newborn or infant screening as a way of ensuring early interventions for FXS.
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Fragile X syndrome affects roughly 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women.
“Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [2]
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- Authors
- Coffee, B., Keith, K., Albizua, I., Malone, T., Mowrey, J., Sherman, S. L., & Warren, S. T.
- Affiliations
- Emory University (US)
- Corresponding author
- Warren, Stephen T.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 85
- Issue
- 4
- Pages
- 503-514
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2756550
- OpenAlex
- W2106750209
- Cited by
- 436
- References
- 52
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 20 · 2023: 16 · 2022: 19 · 2021: 21 · 2020: 26 · 2019: 24 · 2018: 26 · 2017: 41 · 2016: 31 · 2015: 29 · 2014: 35 · 2013: 36 · 2012: 24
- FWCI
- 18.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Association of American Medical Colleges
- National Institutes of Health (HD024064)
- Centers for Disease Control and Prevention
- U.S. Public Health Service (MM-0937-06/06)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, HD020521, R01HD020521, P30HD024064, R37HD020521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- fragile X syndrome, FMR1 gene, CGG repeat expansion, DNA methylation, newborn screening, incidence, Klinefelter syndrome, dried blood spots, intellectual disability, FMR1 full mutation
- MeSH terms
- Base Sequence, DNA, DNA Mutational Analysis, Fragile X Syndrome, Humans, Infant, Newborn, Klinefelter Syndrome, Male, Molecular Sequence Data, Promoter Regions, Genetic, Sensitivity and Specificity, Sequence Homology, Nucleic Acid, Neonatal Screening, DNA Primers, DNA Methylation, Fragile X Messenger Ribonucleoprotein 1
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