title: Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Université Paris Diderot-Paris7, CNRS UMR7216, Epigénétique et Destin Cellulaire, Case Courrier 7042; 35, rue Hélène Brion, 75205 Paris, France. guillaume.velasco@univ-paris-diderot.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Velasco
authors.forename: Emma L
authors.initials: EL
authors.lastname: Walton
authors.forename: Delphine
authors.initials: D
authors.lastname: Sterlin
authors.forename: Sabrine
authors.initials: S
authors.lastname: Hédouin
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nitta
authors.forename: Yuya
authors.initials: Y
authors.lastname: Ito
authors.forename: Fanny
authors.initials: F
authors.lastname: Fouyssac
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Claire
authors.initials: C
authors.lastname: Francastel
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005854:Germ Cells; D018095:Germ-Line Mutation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C552355:MAEL protein, human; D009687:Nuclear Proteins; C504910:SYCE1 protein, mouse; D014157:Transcription Factors
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