title: Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2.
abstract: BACKGROUND
  Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations).
  
  
  OBJECTIVE
  To study the mutation spectrum in ICF syndrome.
  
  
  METHODS
  Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members.
  
  
  RESULTS
  We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients.
  
  
  CONCLUSIONS
  The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort.
  
  
  CONCLUSIONS
  Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M L
authors.identifier: http://orcid.org/0000-0002-3713-5270
authors.initials: ML
authors.lastname: van den Boogaard
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P E
authors.initials: PE
authors.lastname: Thijssen
authors.affiliation: Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Research and Educational Hospital, Ankara, Turkey.
authors.forename: C
authors.initials: C
authors.lastname: Aytekin
authors.affiliation: Department of Paediatrics II, Regina Margherita Hospital Città della Salute e della Scienza di Torino, Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Licciardi
authors.affiliation: Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey.
authors.forename: A A
authors.initials: AA
authors.lastname: Kıykım
authors.affiliation: Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina.
authors.forename: L
authors.initials: L
authors.lastname: Spossito
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.|Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: V A S H
authors.initials: VASH
authors.lastname: Dalm
authors.affiliation: Department of Paediatric Infectious Diseases, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.|Department of Pediatrics, Juliana Children's Hospital, Haga Teaching Hospital, The Hague, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Driessen
authors.affiliation: Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.|Medical service, Stichting Zuidwester, Middelharnis, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kersseboom
authors.affiliation: Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: de Vries
authors.affiliation: Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van Ostaijen-Ten Dam
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Ikinciogullari
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: F
authors.initials: F
authors.lastname: Dogu
authors.affiliation: Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Oleastro
authors.affiliation: Department of Genetics, Hospital "J.P. Garrahan", Buenos Aires, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Bailardo
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Daxinger
authors.affiliation: Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Nain
authors.affiliation: Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Baris
authors.affiliation: Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M J D
authors.initials: MJD
authors.lastname: van Tol
authors.affiliation: Department of Pediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Weemaes
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002503:Centromere / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005145:Face / Q000002:abnormalities / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D063507:Sexism; D055815:Young Adult; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C445325:CDCA7 protein, human; C560314:ZBTB24 protein, human; C412063:HELLS protein, human
keywords: 
  DNMT3B
  ; 
  ICF syndrome; 
  ZBTB24
  ; immunodeficiency