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Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance

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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.

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Acknowledgments

We would like to thank the patients and their families, whose cooperation was essential for the collection of the data used in this study. We thank all the members of the Laboratory of Human Genetics of Infectious Diseases for the helpful discussions and Christine Rivalain, Cécile Patissier, Dominick Papandrea, Dana Liu, and Yelena Nemirovskaya for their assistance. We would also like to thank Annarita Miccio for providing us with the sequences for the GATA2 and GAPDH qPCR primers and Clement KM Ho and Jerome F Strauss for providing us with the modified pRL-SV40-d238 Renilla.

Funding

The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, University of Paris, The Rockefeller University and the St. Giles Foundation, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (R37AI095983), and grants from the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01) and IFNGPHOX (ANR13-ISV3-0001-01 for JB and ACN), GENMSMD (ANR-16-CE17-0005-01 for JB) grants, ECOS-NORD (C19S01-63407 for JB and JFR), and SRC2017 (for JB). CO-Q is supported by ANR-HGDIFD (ANR-14-CE15-006-01). AG was supported by the ANR-IFNGPHOX (ANR13-ISV3-0001-01), GENMSMD (ANR-16-CE17-0005-01), and the Imagine Institute. AC-N and EBO-J are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ grant 303809/2010-8). MMG and RC are supported by Instituto de Salud Carlos III, grants PI11/01086 and PI14/00405, co-financed by the European Regional Development Fund (ERDF). JFR and AAA are supported by Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX; 619-2013, Diana García de Olarte foundation PID and Colciencias grant 713-2016 #111574455633). JR was supported by “Poste d’accueil” INSERM and Imagine Institute.

Author information

Author notes

  1. Edgar Borges de Oliveira-Júnior, Jérémie Rosain, and Franck Rapaport contributed equally to this work.

    Caroline Deswarte, Antoine Guérin, Sairaj Munavar Sajjath, Yu Jerry Zhou, and Stéphane Marot, Claire Lozano contributed equally to this work.

    Aurélie Cobat, Laurent Abel, and Jean-Laurent Casanova contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France

    Carmen Oleaga-Quintas, Edgar Borges de Oliveira-Júnior, Jérémie Rosain, Caroline Deswarte, Antoine Guérin, Anna-Lena Neehus, Manon Roynard, Tom Le Voyer, Anne Puel, Lazaro Lorenzo-Diaz, Stéphanie Boisson-Dupuis, Guillaume Vogt, Aurélie Cobat, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  2. University of Paris, Imagine Institute, Paris, France

    Carmen Oleaga-Quintas, Edgar Borges de Oliveira-Júnior, Jérémie Rosain, Caroline Deswarte, Antoine Guérin, Anna-Lena Neehus, Manon Roynard, Tom Le Voyer, Anne Puel, Lazaro Lorenzo-Diaz, Stéphanie Boisson-Dupuis, Guillaume Vogt, Aurélie Cobat, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  3. Department of Immunology, School of Medicine, Complutense University, Madrid, Spain

    Carmen Oleaga-Quintas

  4. Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil

    Edgar Borges de Oliveira-Júnior & Antonio Condino-Neto

  5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Franck Rapaport, Andrés Augusto Arias, Marcela Moncada-Vélez, Anne Puel, Noé Ramirez Alejo, Stéphanie Boisson-Dupuis, Rubén Martínez-Barricarte, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  6. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA

    Sairaj Munavar Sajjath, Yu Jerry Zhou & Kang Liu

  7. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France

    Stéphane Marot, Claire Lozano, Alexis Cuffel & Jacinta Bustamante

  8. Department of Immunology, Porto Hospital Center, Porto, Portugal

    Lidia Branco & Julia Vasconcelos

  9. Service of Infectious Diseases, University Hospital Vall d’Hebron, Barcelona, Spain

    Nuria Fernández-Hidalgo

  10. The Children’s Foundation Research Center and Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA

    Dukhee Betty Lew & Kacy A. Ramirez

  11. Infectious Diseases Unit, Montpellier, France

    Anne-Sophie Brunel & Marie-Gabrielle Vigué

  12. Pediatric Oncology and Hematology, University Hospital of Nantes, Nantes, France

    Caroline Thomas & Elise Launay

  13. Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UdeA, Medellin, Colombia

    Andrés Augusto Arias & José Franco Restrepo

  14. School of Microbiology, University of Antioquia UdeA, Medellin, Colombia

    Andrés Augusto Arias

  15. Department of Immunology, Son Espases Hospital, Palma de Mallorca, Spain

    Vanesa Cunill Monjo

  16. Department of Pediatrics, Porto Hospital Center, Porto, Portugal

    Laura Marques

  17. Department of Dermatology, Ege University Medical Faculty, İzmir, Turkey

    Bengü Gerçeker

  18. Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Jeffrey Model Foundation Excellence Center, Barcelona, Spain

    Roger Colobran & Mónica Martínez-Gallo

  19. Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

    Roger Colobran & Mónica Martínez-Gallo

  20. Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain

    Roger Colobran & Mónica Martínez-Gallo

  21. Area of Clinical and Molecular Genetics, University Hospital Vall d’Hebron, Barcelona, Spain

    Roger Colobran

  22. Immunodeficiencies Research Unit at the National Institute of Pediatrics, Mexico City, Mexico

    Gabriela Lopez-Herrera & Laura Berron-Ruiz

  23. Allergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico

    Nora Hilda Segura Méndez & Patricia O’Farrill Romanillos

  24. Department of Genetics, DMU BioGeM, Pitié Salpetrière Hospital, AP-HP, Paris, France

    Christine Bellanné-Chantelot

  25. St Jude Children’s Research Hospital, 262 Danny Thomas Place, IRC Room E8061 Mail Stop 320, Memphis, TN, 38105, USA

    Kacy A. Ramirez

  26. LeBonheur Children’s Hospital, West Patient Tower, Rm 433, Memphis, TN, 38103, USA

    Kacy A. Ramirez

  27. Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain

    Rebeca Pérez de Diego

  28. National Center for Bone Marrow Grafts, Tunis Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia

    Fethi Mellouli

  29. Department of Immunology, Gran Canaria Dr. Negrin University Hospital, Las Palmas de Gran Canaria, Spain

    Carlos Rodriguez-Gallego

  30. Clinic of Immunology and Rheumatology, Medical School of Hannover, Hannover, Germany

    Torsten Witte

  31. Department of Immunology, Clinicas Hospital of Porto Alegre, Porto Alegre, RS, Brazil

    Mariana Jobim & Luiz Fernando Jobim

  32. Department of Pediatrics, Infectious Diseases and Immunology, CHU Montpellier, Montpellier, France

    Eric Jeziorski

  33. Department of Hematology and Internal Medicine, Saint Louis Hospital, AP-HP, Paris, France

    Claire Fieschi

  34. Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France

    Jean Donadieu

  35. Department of Pediatric Hematology and Immunology, CHU Toulouse, Toulouse, France

    Marlène Pasquet

  36. Center of Research in Cancerology, INSERM U1037, Team 16, IUCT-Oncopole, Toulouse, France

    Marlène Pasquet

  37. Internal Medicine Allergy and Clinical Immunology, Medical School of Ege, Izmir, Turkey

    Fatma Omur Ardeniz

  38. Department of Allergy and Clinical Immunology, Medical School, Federal University of Bahia, Salvador, BA, Brazil

    Regis A. Campos

  39. Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Luiz Fernando Jobim

  40. Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA

    Kang Liu

  41. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova

  42. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

Authors
  1. Carmen Oleaga-Quintas
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  2. Edgar Borges de Oliveira-Júnior
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  3. Jérémie Rosain
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  4. Franck Rapaport
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  5. Caroline Deswarte
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  6. Antoine Guérin
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  7. Sairaj Munavar Sajjath
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  8. Yu Jerry Zhou
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  9. Stéphane Marot
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  10. Claire Lozano
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  11. Lidia Branco
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  12. Nuria Fernández-Hidalgo
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  13. Dukhee Betty Lew
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  14. Anne-Sophie Brunel
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  15. Caroline Thomas
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  16. Elise Launay
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  17. Andrés Augusto Arias
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  18. Alexis Cuffel
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  19. Vanesa Cunill Monjo
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  20. Anna-Lena Neehus
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  21. Laura Marques
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  23. Marcela Moncada-Vélez
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  27. Gabriela Lopez-Herrera
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  28. Laura Berron-Ruiz
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  29. Nora Hilda Segura Méndez
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  36. Noé Ramirez Alejo
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  37. Rebeca Pérez de Diego
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  38. Antonio Condino-Neto
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  39. Fethi Mellouli
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  40. Carlos Rodriguez-Gallego
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  41. Torsten Witte
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  42. José Franco Restrepo
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  43. Mariana Jobim
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  44. Stéphanie Boisson-Dupuis
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  50. Julia Vasconcelos
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  51. Fatma Omur Ardeniz
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  52. Mónica Martínez-Gallo
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  53. Regis A. Campos
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  55. Rubén Martínez-Barricarte
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  56. Kang Liu
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  57. Aurélie Cobat
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  58. Laurent Abel
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  60. Jacinta Bustamante
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Contributions

CO-Q, EBO-J, CD, GV, AG, SM, CL, SMS, KG, and RM-B carried out the experiments. FR and LA performed the purifying selection studies. AC performed the penetrance calculations. JR, LB, NF-H, DBL, ASB, CT, EL, AAA, AC, CBC, TL, ALN, LLD, JR, VCM, LM, MR, MM-V, BG, RC, MGV, GL-H, LB-R, NHSM, POFR, AP, KAR, NRA, RPD, AC-N, FM, CR-G, TW, JFR, MJ, SB-D, EJ, CF, JD, MP, JV, FOA, MM-G, RAC, and LFJ were responsible for the clinical and biological evaluation. JB designed the study and contributed intellectually to the process. CO-Q, JB, and J-LC wrote the manuscript. All authors commented on and discussed the paper.

Corresponding author

Correspondence to Jacinta Bustamante.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants

Informed consent for participation in this study was obtained in accordance with local regulations, with approval from the IRB. The experiments described here were performed in Mexico and France, in accordance with local regulations.

Informed Consent

Written informed consent was obtained from the guardians of the pediatric patients or directly from adult patients.

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Oleaga-Quintas, C., de Oliveira-Júnior, E.B., Rosain, J. et al. Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance. J Clin Immunol 41, 639–657 (2021). https://doi.org/10.1007/s10875-020-00930-3

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