Edgar Borges de Oliveira-Júnior1,2,3, Jérémie Rosain1,2, Franck Rapaport4, Caroline Deswarte1,2, Antoine Guérin1,2, Sairaj Munavar Sajjath5, Yu Jerry Zhou5, Stéphane Marot6, Claire Lozano6, Aurélie Cobat1,2, Laurent Abel1,2,4, Jean-Laurent Casanova1,2,4,7,8, Carmen Oleaga-Quintas1,2,9, Lidia Branco10, Nuria Fernández-Hidalgo11, Dukhee Betty Lew12, Anne-Sophie Brunel13, Caroline Thomas14, Elise Launay14, Andrés Augusto Arias4,15,16, Alexis Cuffel6, Vanesa Cunill Monjo17, Anna-Lena Neehus1,2, Laura Marques18, Manon Roynard1,2, Marcela Moncada-Vélez4, Bengü Gerçeker19, Roger Colobran20,21,22,23, Marie-Gabrielle Vigué13, Gabriela Lopez-Herrera24, Laura Berron-Ruiz24, Nora Hilda Segura Méndez25, Patricia O'Farrill Romanillos25, Tom Le Voyer1,2, Anne Puel1,2,4, Christine Bellanné-Chantelot26, Kacy A Ramirez12,27,28, Lazaro Lorenzo-Diaz1,2, Noé Ramirez Alejo4, Rebeca Pérez de Diego29, Antonio Condino-Neto3, Fethi Mellouli30, Carlos Rodriguez-Gallego31, Torsten Witte32, José Franco Restrepo15, Mariana Jobim33, Stéphanie Boisson-Dupuis1,2,4, Eric Jeziorski34, Claire Fieschi35, Guillaume Vogt1,2, Jean Donadieu36, Marlène Pasquet37,38, Julia Vasconcelos10, Fatma Omur Ardeniz39, Mónica Martínez-Gallo20,21,22, Regis A Campos40, Luiz Fernando Jobim33,41, Rubén Martínez-Barricarte4, Kang Liu5,42, Jacinta Bustamante43,44,45,46. 1. Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France. 2. University of Paris, Imagine Institute, Paris, France. 3. Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil. 4. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 5. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA. 6. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. 7. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France. 8. Howard Hughes Medical Institute, New York, NY, USA. 9. Department of Immunology, School of Medicine, Complutense University, Madrid, Spain. 10. Department of Immunology, Porto Hospital Center, Porto, Portugal. 11. Service of Infectious Diseases, University Hospital Vall d'Hebron, Barcelona, Spain. 12. The Children's Foundation Research Center and Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA. 13. Infectious Diseases Unit, Montpellier, France. 14. Pediatric Oncology and Hematology, University Hospital of Nantes, Nantes, France. 15. Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UdeA, Medellin, Colombia. 16. School of Microbiology, University of Antioquia UdeA, Medellin, Colombia. 17. Department of Immunology, Son Espases Hospital, Palma de Mallorca, Spain. 18. Department of Pediatrics, Porto Hospital Center, Porto, Portugal. 19. Department of Dermatology, Ege University Medical Faculty, İzmir, Turkey. 20. Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Jeffrey Model Foundation Excellence Center, Barcelona, Spain. 21. Vall d'Hebron Research Institute (VHIR), Barcelona, Spain. 22. Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain. 23. Area of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain. 24. Immunodeficiencies Research Unit at the National Institute of Pediatrics, Mexico City, Mexico. 25. Allergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico. 26. Department of Genetics, DMU BioGeM, Pitié Salpetrière Hospital, AP-HP, Paris, France. 27. St Jude Children's Research Hospital, 262 Danny Thomas Place, IRC Room E8061 Mail Stop 320, Memphis, TN, 38105, USA. 28. LeBonheur Children's Hospital, West Patient Tower, Rm 433, Memphis, TN, 38103, USA. 29. Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain. 30. National Center for Bone Marrow Grafts, Tunis Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia. 31. Department of Immunology, Gran Canaria Dr. Negrin University Hospital, Las Palmas de Gran Canaria, Spain. 32. Clinic of Immunology and Rheumatology, Medical School of Hannover, Hannover, Germany. 33. Department of Immunology, Clinicas Hospital of Porto Alegre, Porto Alegre, RS, Brazil. 34. Department of Pediatrics, Infectious Diseases and Immunology, CHU Montpellier, Montpellier, France. 35. Department of Hematology and Internal Medicine, Saint Louis Hospital, AP-HP, Paris, France. 36. Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France. 37. Department of Pediatric Hematology and Immunology, CHU Toulouse, Toulouse, France. 38. Center of Research in Cancerology, INSERM U1037, Team 16, IUCT-Oncopole, Toulouse, France. 39. Internal Medicine Allergy and Clinical Immunology, Medical School of Ege, Izmir, Turkey. 40. Department of Allergy and Clinical Immunology, Medical School, Federal University of Bahia, Salvador, BA, Brazil. 41. Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. 42. Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA. 43. Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France. jacinta.bustamante@inserm.fr. 44. University of Paris, Imagine Institute, Paris, France. jacinta.bustamante@inserm.fr. 45. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. jacinta.bustamante@inserm.fr. 46. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr.
Abstract
PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
Authors: Philipp A Greif; Annika Dufour; Nikola P Konstandin; Bianka Ksienzyk; Evelyn Zellmeier; Belay Tizazu; Jutta Sturm; Tobias Benthaus; Tobias Herold; Marjan Yaghmaie; Petra Dörge; Karl-Peter Hopfner; Andreas Hauser; Alexander Graf; Stefan Krebs; Helmut Blum; Purvi M Kakadia; Stephanie Schneider; Eva Hoster; Friederike Schneider; Martin Stanulla; Jan Braess; Maria Cristina Sauerland; Wolfgang E Berdel; Thomas Büchner; Bernhard J Woermann; Wolfgang Hiddemann; Karsten Spiekermann; Stefan K Bohlander Journal: Blood Date: 2012-05-30 Impact factor: 22.113
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Authors: Alexander Simonis; Michaela Fux; Gayathri Nair; Nicolas J Mueller; Eugenia Haralambieva; Thomas Pabst; Jana Pachlopnik Schmid; Adrian Schmidt; Urs Schanz; Markus G Manz; Antonia M S Müller Journal: Ann Hematol Date: 2018-06-13 Impact factor: 3.673
Authors: Karthik A Ganapathi; Danielle M Townsley; Amy P Hsu; Diane C Arthur; Christa S Zerbe; Jennifer Cuellar-Rodriguez; Dennis D Hickstein; Sergio D Rosenzweig; Raul C Braylan; Neal S Young; Steven M Holland; Katherine R Calvo Journal: Blood Date: 2014-10-30 Impact factor: 22.113
Authors: Jean Donadieu; Marie Lamant; Claire Fieschi; Flore Sicre de Fontbrune; Aurélie Caye; Marie Ouachee; Blandine Beaupain; Jacinta Bustamante; Hélène A Poirel; Bertrand Isidor; Eric Van Den Neste; Antoine Neel; Stanislas Nimubona; Fabienne Toutain; Vincent Barlogis; Nicolas Schleinitz; Thierry Leblanc; Pierre Rohrlich; Felipe Suarez; Dana Ranta; Wadih Abou Chahla; Bénédicte Bruno; Louis Terriou; Sylvie Francois; Bruno Lioure; Guido Ahle; Françoise Bachelerie; Claude Preudhomme; Eric Delabesse; Hélène Cave; Christine Bellanné-Chantelot; Marlène Pasquet Journal: Haematologica Date: 2018-05-03 Impact factor: 9.941