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

Author(s):Show less -

Oleaga-Quintas, Carmen ^{[1, 2, 3]} ; de Oliveira-Junior, Edgar Borges ^{[1, 2, 3]} ; Rosain, Jeremie ^{[1, 2]} ; Rapaport, Franck ^[4] ; Deswarte, Caroline ^{[1, 2]} ; Guerin, Antoine ^{[1, 2]} ; Sajjath, Sairaj Munavar ^[5] ; Zhou, Yu Jerry ^[5] ; Marot, Stephane ^[6] ; Lozano, Claire ^[6] ; Branco, Lidia ^[7] ; Fernandez-Hidalgo, Nuria ^[8] ; Lew, Dukhee Betty ^{[9, 10]} ; Brunel, Anne-Sophie ^[11] ; Thomas, Caroline ^[12] ; Launay, Elise ^[12] ; Arias, Andres Augusto ^{[4, 13, 14]} ; Cuffel, Alexis ^[6] ; Monjo, Vanesa Cunill ^[15] ; Neehus, Anna-Lena ^{[1, 2]} ; Marques, Laura ^[16] ; Roynard, Manon ^{[1, 2]} ; Moncada-Velez, Marcela ^[4] ; Gerceker, Bengu ^[17] ; Colobran, Roger ^{[18, 19, 20, 21]} ; Vigue, Marie-Gabrielle ^[11] ; Lopez-Herrera, Gabriela ^[22] ; Berron-Ruiz, Laura ^[22] ; Mendez, Nora Hilda Segura ^[23] ; O'Farrill Romanillos, Patricia ^[23] ; Le Voyer, Tom ^{[1, 2]} ; Puel, Anne ^{[4, 1, 2]} ; Bellanne-Chantelot, Christine ^[24] ; Ramirez, Kacy A. ^{[9, 10, 25, 26]} ; Lorenzo-Diaz, Lazaro ^{[1, 2]} ; Alejo, Noe Ramirez ^[4] ; de Diego, Rebeca Perez ^[27] ; Condino-Neto, Antonio ^[28] ; Mellouli, Fethi ^[29] ; Rodriguez-Gallego, Carlos ^[30] ; Witte, Torsten ^[31] ; Restrepo, Jose Franco ^[13] ; Jobim, Mariana ^[32] ; Boisson-Dupuis, Stephanie ^{[4, 1, 2]} ; Jeziorski, Eric ^[33] ; Fieschi, Claire ^[34] ; Vogt, Guillaume ^{[1, 2]} ; Donadieu, Jean ^[35] ; Pasquet, Marlene ^{[36, 37]} ; Vasconcelos, Julia ^[7] ; Ardeniz, Fatma Omur ^[38] ; Martinez-Gallo, Monica ^{[18, 19, 20]} ; Campos, Regis A. ^[39] ; Jobim, Luiz Fernando ^{[40, 32]} ; Martinez-Barricarte, Ruben ^[4] ; Liu, Kang ^{[5, 41]} ; Cobat, Aurelie ^{[1, 2]} ; Abel, Laurent ^{[4, 1, 2]} ; Casanova, Jean-Laurent ^{[42, 4, 43, 1, 2]} ; Bustamante, Jacinta ^{[6, 4, 1, 2]}

Affiliation:Show less -

^[1] Necker Hosp Sick Children, Lab Human Genet Infect Dis, INSERM, U1163, 24 Blvd Montparnasse, Paris - France

^[2] Univ Paris, Imagine Inst, Paris - France

^[3] Univ Complutense Madrid, Sch Med, Dept Immunol, Madrid - Spain

^[4] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 - USA

^[5] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY - USA

^[6] Necker Hosp Sick Children, AP HP, Ctr Study Primary Immunodeficiencies, Paris - France

^[7] Porto Hosp Ctr, Dept Immunol, Porto - Portugal

^[8] Univ Hosp Vall dHebron, Serv Infect Dis, Barcelona - Spain

^[9] Univ Tennessee, Coll Med, Childrens Fdn Res Ctr, Memphis, TN - USA

^[10] Univ Tennessee, Coll Med, Dept Pediat, Memphis, TN - USA

^[11] Infect Dis Unit, Montpellier - France

^[12] Univ Hosp Nantes, Pediat Oncol & Hematol, Nantes - France

^[13] Univ Antioquia UdeA, Sch Med, Dept Microbiol & Parasitol, Primary Immunodeficiencies Grp, Medellin - Colombia

^[14] Univ Antioquia UdeA, Sch Microbiol, Medellin - Colombia

^[15] Son Espases Hosp, Dept Immunol, Palma De Mallorca - Spain

^[16] Porto Hosp Ctr, Dept Pediat, Porto - Portugal

^[17] Ege Univ, Dept Dermatol, Med Fac, Izmir - Turkey

^[18] Vall dHebron Res Inst VHIR, Barcelona - Spain

^[19] Hosp Univ Vall dHebron HUVH, Immunol Div, Jeffrey Model Fdn Excellence Ctr, Barcelona - Spain

^[20] Autonomous Univ Barcelona UAB, Dept Cell Biol Physiol & Immunol, Barcelona - Spain

^[21] Univ Hosp Vall dHebron, Area Clin & Mol Genet, Barcelona - Spain

^[22] Natl Inst Pediat, Immunodeficiencies Res Unit, Mexico City, DF - Mexico

^[23] Mexican Inst Social Secur IMSS, XXI Century Natl Med Ctr, Allergy & Clin Immunol Serv, Mexico City, DF - Mexico

^[24] Hop La Pitie Salpetriere, AP HP, Dept Genet, DMU BioGeM, Paris - France

^[25] St Jude Childrens Res Hosp, 262 Danny Thomas Pl, IRC Room E8061 Mail Stop 320, Memphis, TN 38105 - USA

^[26] LeBonheur Childrens Hosp, West Patient Tower, Rm 433, Memphis, TN 38103 - USA

^[27] La Paz Univ Hosp, IdiPAZ Inst Hlth Res, Lab Immunogenet Human Dis, Madrid - Spain

^[28] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP - Brazil

^[29] Univ Tunis El Manar, Tunis Fac Med, Natl Ctr Bone Marrow Grafts, Tunis - Tunisia

^[30] Gran Canaria Dr Negrin Univ Hosp, Dept Immunol, Las Palmas Gran Canaria - Spain

^[31] Med Sch Hannover, Clin Immunol & Rheumatol, Hannover - Germany

^[32] Clin Hosp Porto Alegre, Dept Immunol, Porto Alegre, RS - Brazil

^[33] CHU Montpellier, Dept Pediat Infect Dis & Immunol, Montpellier - France

^[34] St Louis Hosp, AP HP, Dept Hematol & Internal Med, Paris - France

^[35] Trousseau Hosp, AP HP, Dept Pediat Hematol & Oncol, Paris - France

^[36] CHU Toulouse, Dept Pediat Hematol & Immunol, Toulouse - France

^[37] IUCT Oncopole, Ctr Res Cancerol, INSERM, Team 16, U1037, Toulouse - France

^[38] Med Sch Ege, Internal Med Allergy & Clin Immunol, Izmir - Turkey

^[39] Univ Fed Bahia, Med Sch, Dept Allergy & Clin Immunol, Salvador, BA - Brazil

^[40] Univ Fed Rio Grande do Sul, Sch Med, Dept Internal Med, Porto Alegre, RS - Brazil

^[41] Boehringer Ingelheim Pharmaceut, Dept Canc Immunol & Immune Modulat, Ridgefield, CT - USA

^[42] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris - France

^[43] Howard Hughes Med Inst, New York, NY - USA

• Document type: Journal article
• Source: JOURNAL OF CLINICAL IMMUNOLOGY; v. 41, n. 3 JAN 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 12/11757-2 - Genetic and functional evaluation of novel genes associated with Mendelian susceptibility to mycobacterial infections
• Grantee: Edgar Borges de Oliveira Junior
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 10/51814-0 - Human genetics in mycobacterial infections: new molecular genetic defects involved in Mendelian susceptibility to mycobacterial infections
• Grantee: Antonio Condino Neto
• Support Opportunities: Regular Research Grants