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Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

Daria Grafodatskaya1, Barian HY Chung23, Darci T Butcher1, Andrei L Turinsky4, Sarah J Goodman3, Sana Choufani3, Yi-An Chen1, Youliang Lou1, Chunhua Zhao1, Rageen Rajendram1, Fatima E Abidi5, Cindy Skinner5, James Stavropoulos6, Carolyn A Bondy7, Jill Hamilton89, Shoshana Wodak104, Stephen W Scherer1011, Charles E Schwartz5 and Rosanna Weksberg29*

Author Affiliations

1 Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada

2 Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada

3 Centre of Reproduction, Growth & Development, Department of Pediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, Hong Kong

4 Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada

5 J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC, USA

6 Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada

7 Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

8 Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada

9 Department of Pediatrics, University of Toronto, Toronto, ON, Canada

10 Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON, Canada

11 The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada

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BMC Medical Genomics 2013, 6:1  doi:10.1186/1755-8794-6-1

Published: 28 January 2013



A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.


Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.


We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.

KDM5C; DNA methylation; H3K4 methylation; Intellectual disability