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Epigenetics Chromatin. 2017 Mar 10;10:10. doi: 10.1186/s13072-017-0118-4. eCollection 2017.

Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome.

Author information

1
Department of Pathology and Lab Medicine, Western University, London, ON Canada.
2
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON Canada.
3
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.
4
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.
5
Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Center, 800 Commissioner's Road E, B10-104, London, ON N6A 5W9 Canada.
6
Department of Paediatrics, Western University, London, ON Canada.
7
Department of Biochemistry, Western University, London, ON Canada.
8
Department of Oncology, Western University, London, ON Canada.
9
Children's Health Research Institute, London, ON Canada.
10
Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC USA.

Abstract

BACKGROUND:

Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the ATRX gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.

RESULTS:

We performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.

CONCLUSION:

Most significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with ATRX gene sequence variants of unknown significance.

KEYWORDS:

ATRX; Biomarker; DNA methylation; Epi-signature; Intellectual disability

PMID:
28293299
PMCID:
PMC5345252
DOI:
10.1186/s13072-017-0118-4
[Indexed for MEDLINE]
Free PMC Article

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