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Open Access Highly Accessed Research article

Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus

Reid S Alisch25, Tao Wang12, Pankaj Chopra2, Jeannie Visootsak24, Karen N Conneely2 and Stephen T Warren234*

Author Affiliations

1 Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA, 30322, USA

2 Departments of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

3 Departments of Biochemistry, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

4 Departments of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

5 Current address: Department of Psychiatry, University of Wisconsin–Madison, Madison, WI, 53719, USA

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BMC Medical Genetics 2013, 14:18  doi:10.1186/1471-2350-14-18

Published: 29 January 2013

Abstract

Background

Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by an expansion of CGG repeats located in the 5 untranslated region (UTR) of the FMR1 gene, which leads to hypermethylation and silencing of this locus. Although a dramatic increase in DNA methylation of the FMR1 full mutation allele is well documented, the extent to which these changes affect DNA methylation throughout the rest of the genome has gone unexplored.

Methods

Here we examined genome-wide methylation in both peripheral blood (N = 62) and induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls.

Results

We not only found the expected significant DNA methylation differences in the FMR1 promoter and 5 UTR, we also saw that these changes inverse in the FMR1 gene body. Importantly, we found no other differentially methylated loci throughout the remainder of the genome, indicating the aberrant methylation of FMR1 in FXS is locus-specific.

Conclusions

This study provides a comprehensive methylation profile of FXS and helps refine our understanding of the mechanisms behind FMR1 silencing.

Keywords:
Epigenetics; DNA methylation; Fragile X syndrome