Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2

Clinical Genetics - Tập 92 Số 4 - Trang 380-387 - 2017
Marlinde L. van den Boogaard1, Peter Thijssen2,1, Caner Aytekin3, Francesco Licciardi4, Ayça Kıykım5, Lucía Spossito6, Virgil A. S. H. Dalm7,8, Gertjan J. Driessen9,10, Rogier Kersseboom11,12, Femke de Vries11, M.M. van Ostaijen‐ten Dam13, Aydan İkincioğulları14, Figen Doğu14, Matías Oleastro6, E. Bailardo15, Lucia Daxinger1, Ercan Nain5, Safa Barış5, Maarten J. D. van Tol13, Corry M.R. Weemaes16, Silvère M. van der Maarel1
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
2Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
3Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children’s, Research and Educational Hospital, Ankara, Turkey
4Department of Paediatrics II Regina Margherita Hospital Città della Salute e della Scienza di Torino Torino Italy
5Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
6Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina
7Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands
8Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
9Department of Paediatric Infectious Diseases, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
10Department of Pediatrics, Juliana Children’s Hospital, Haga Teaching Hospital, The Hague, The Netherlands
11Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
12Medical service, Stichting Zuidwester, Middelharnis, The Netherlands
13Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands
14Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
15Department of Genetics, Hospital "J.P. Garrahan", Buenos Aires, Argentina
16Department of Pediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Tóm tắt

BackgroundImmunodeficiency, 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).AimTo study the mutation spectrum in ICF syndrome.Materials and methodsGenetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members.ResultsWe 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.DiscussionThe 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.ConclusionOur study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.

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Clinical Genetics

Tập 92 Số 4

380-387

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