• Carmen Oleaga-Quintas, Edgar Borges de Oliveira-Júnior, Jérémie Rosain, Franck Rapaport, Caroline Deswarte, Antoine Guérin, Sairaj Munavar Sajjath, Yu Jerry Zhou, Stéphane Marot, Claire Lozano, Lidia Branco, Nuria Fernández-Hidalgo, Dukhee Betty Lew, Anne-Sophie Brunel, Caroline Thomas, Elise Launay, Andrés Augusto Arias, Alexis Cuffel, Vanesa Cunill Monjo, Anna-Lena Neehus, Laura Marques, Manon Roynard, Marcela Moncada-Vélez, Bengü Gerçeker, Roger Colobran, Marie-Gabrielle Vigué, Gabriela Lopez-Herrera, Laura Berron-Ruiz, MéndezNora Hilda SeguraNHSAllergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico., Patricia O'Farrill Romanillos, Tom Le Voyer, Anne Puel, Christine Bellanné-Chantelot, Kacy A Ramirez, Lazaro Lorenzo-Diaz, Noé Ramirez Alejo, de DiegoRebeca PérezRPLaboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain., Antonio Condino-Neto, Fethi Mellouli, Carlos Rodriguez-Gallego, Torsten Witte, José Franco Restrepo, Mariana Jobim, Stéphanie Boisson-Dupuis, Eric Jeziorski, Claire Fieschi, Guillaume Vogt, Jean Donadieu, Marlène Pasquet, Julia Vasconcelos, Fatma Omur Ardeniz, Mónica Martínez-Gallo, Regis A Campos, Luiz Fernando Jobim, Rubén Martínez-Barricarte, Kang Liu, Aurélie Cobat, Laurent Abel, Jean-Laurent Casanova, and Jacinta Bustamante.
• Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France.
• J. Clin. Immunol. 2021 Apr 1; 41 (3): 639-657.

PurposeGermline 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.MethodsWe enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.ResultsWe 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.ConclusionClinical 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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