title: Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome.
abstract: Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator geneATRX. 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 theATRXgene 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.
  
  
  
  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.
  
  
  
  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 withATRXgene sequence variants of unknown significance.
authors.affiliation: Department of Pathology and Lab Medicine, Western University, London, ON Canada.
authors.forename: Laila C
authors.initials: LC
authors.lastname: Schenkel
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON Canada.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Kernohan
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON Canada.
authors.forename: Arran
authors.initials: A
authors.lastname: McBride
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.|Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.
authors.forename: Ditta
authors.initials: D
authors.lastname: Reina
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.|Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hodge
authors.affiliation: Department of Pathology and Lab Medicine, Western University, London, ON Canada.|Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Center, 800 Commissioner's Road E, B10-104, London, ON N6A 5W9 Canada.|Department of Paediatrics, Western University, London, ON Canada.|Department of Biochemistry, Western University, London, ON Canada.|Department of Oncology, Western University, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ainsworth
authors.affiliation: Department of Paediatrics, Western University, London, ON Canada.|Department of Biochemistry, Western University, London, ON Canada.|Department of Oncology, Western University, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: David I
authors.initials: DI
authors.lastname: Rodenhiser
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.|Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pare
authors.affiliation: Department of Paediatrics, Western University, London, ON Canada.|Department of Biochemistry, Western University, London, ON Canada.|Department of Oncology, Western University, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.affiliation: Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Skinner
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.affiliation: Department of Pathology and Lab Medicine, Western University, London, ON Canada.|Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Center, 800 Commissioner's Road E, B10-104, London, ON N6A 5W9 Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: Bekim
authors.initials: B
authors.lastname: Sadikovic
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D000075924:X-linked Nuclear Protein / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D017085:alpha-Thalassemia / Q000235:genetics* / Q000473:pathology
chemical_list: D004247:DNA; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; Biomarker; DNA methylation; Epi-signature; Intellectual disability