M L van den Boogaard1, P E Thijssen1,2, C Aytekin3, F Licciardi4, A A Kıykım5, L Spossito6, V A S H Dalm7,8, G J Driessen9,10, R Kersseboom11,12, F de Vries11, M M van Ostaijen-Ten Dam13, A Ikinciogullari14, F Dogu14, M Oleastro6, E Bailardo15, L Daxinger1, E Nain5, S Baris5, M J D van Tol13, C Weemaes16, S M van der Maarel1. 1. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 2. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 3. Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Research and Educational Hospital, Ankara, Turkey. 4. Department of Paediatrics II, Regina Margherita Hospital Città della Salute e della Scienza di Torino, Torino, Italy. 5. Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey. 6. Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina. 7. Department of Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. 8. Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. 9. Department of Paediatric Infectious Diseases, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. 10. Department of Pediatrics, Juliana Children's Hospital, Haga Teaching Hospital, The Hague, The Netherlands. 11. Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. 12. Medical service, Stichting Zuidwester, Middelharnis, The Netherlands. 13. Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands. 14. Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey. 15. Department of Genetics, Hospital "J.P. Garrahan", Buenos Aires, Argentina. 16. Department of Pediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND 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. DISCUSSION: 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. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
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). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS: Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICFpatients and family members. RESULTS: We describe 7 ICF1patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2patients, 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. DISCUSSION: The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2patients 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. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
Authors: Hamza A Alghamdi; Suha A Tashkandi; Eman M Alidrissi; Rawan D Aledielah; Khelad A AlSaidi; Enas S Alharbi; Murad K Habazi; Mofareh S Alzahrani Journal: J Clin Immunol Date: 2018-12-03 Impact factor: 8.317
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Authors: Angela Helfricht; Peter E Thijssen; Magdalena B Rother; Rashmi G Shah; Likun Du; Sanami Takada; Mélanie Rogier; Jacques Moritz; Hanna IJspeert; Chantal Stoepker; Monique M van Ostaijen-Ten Dam; Vincent Heyer; Martijn S Luijsterburg; Anton de Groot; Rianca Jak; Gwendolynn Grootaers; Jun Wang; Pooja Rao; Alfred C O Vertegaal; Maarten J D van Tol; Qiang Pan-Hammarström; Bernardo Reina-San-Martin; Girish M Shah; Mirjam van der Burg; Silvère M van der Maarel; Haico van Attikum Journal: J Exp Med Date: 2020-11-02 Impact factor: 14.307