Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

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• 作者：Guillaume Velasco (1)
  Emma L Walton (1)
  Delphine Sterlin (2)
  Sabrine H茅douin (1)
  Hirohisa Nitta (5)
  Yuya Ito (5)
  Fanny Fouyssac (6)
  Andr茅 M茅garban茅 (7)
  Hiroyuki Sasaki (5)
  Capucine Picard (2) (3) (4)
  Claire Francastel (1)
  
  1. Epig茅n茅tique et Destin Cellulaire ; Universit茅 Paris Diderot-Paris7 ; CNRS UMR7216 ; Case Courrier 7042 ; 35 ; rue H茅l猫ne Brion ; 75205 ; Paris ; France
  2. Center for the Study of Primary Immunodeficiencies ; Assistance Publique-H么pitaux de Paris ; Necker Hospital ; Paris ; France
  5. Division of Epigenomics and Development ; Department of Molecular Genetics ; Medical Institute of Bioregulation ; Kyushu University ; Fukuoka ; Japan
  6. Service d鈥橦茅mato-oncologie P茅diatrique et Transplantations M茅dullaires ; Centre Hospitalier Universitaire de Nancy ; H么pital Brabois Enfants ; Vand艙uvre-l猫s-Nancy ; France
  7. Unit茅 de G茅n茅tique M茅dicale et laboratoire associ茅 ; INSERM UMR S_910 ; Facult茅 de M茅decine ; Universit茅 Saint Joseph ; Beirut ; Lebanon
  3. Institut National de la Sant茅 et de la Recherche M茅dicale ; Laboratory of Human Genetics of Infectious Diseases ; Necker Branch ; U980 ; Paris ; France
  4. Imagine Institute ; University Paris Descartes ; Sorbonne Paris Cit茅 ; Paris ; France
  
• 关键词：Agammaglobulinemia ; DNA methylation ; Heterochromatin ; DNA ; Satellite ; Gene expression ; Biological markers/diagnosis use ; Biological markers/etiology ; Genes ; X ; linked
• 刊名：Orphanet Journal of Rare Diseases
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：9
• 期：1
• 全文大小：246 KB
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• 刊物主题：Medicine/Public Health, general; Pharmacology/Toxicology; Medicinal Chemistry;
• 出版者：BioMed Central
• ISSN：1750-1172

文摘

Background Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease. Method We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients. Results We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease. Conclusions Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome.