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

• Published in: Journal of clinical immunology Vol. 41; no. 3; pp. 639 - 657
• Main Authors: Oleaga-Quintas, Carmen, de Oliveira-Júnior, Edgar Borges, Rosain, Jérémie, Rapaport, Franck, Deswarte, Caroline, Guérin, Antoine, Sajjath, Sairaj Munavar, Zhou, Yu Jerry, Marot, Stéphane, Lozano, Claire, Branco, Lidia, Fernández-Hidalgo, Nuria, Lew, Dukhee Betty, Brunel, Anne-Sophie, Thomas, Caroline, Launay, Elise, Arias, Andrés Augusto, Cuffel, Alexis, Monjo, Vanesa Cunill, Neehus, Anna-Lena, Marques, Laura, Roynard, Manon, Moncada-Vélez, Marcela, Gerçeker, Bengü, Colobran, Roger, Vigué, Marie-Gabrielle, Lopez-Herrera, Gabriela, Berron-Ruiz, Laura, Méndez, Nora Hilda Segura, O’Farrill Romanillos, Patricia, Le Voyer, Tom, Puel, Anne, Bellanné-Chantelot, Christine, Ramirez, Kacy A., Lorenzo-Diaz, Lazaro, Alejo, Noé Ramirez, de Diego, Rebeca Pérez, Condino-Neto, Antonio, Mellouli, Fethi, Rodriguez-Gallego, Carlos, Witte, Torsten, Restrepo, José Franco, Jobim, Mariana, Boisson-Dupuis, Stéphanie, Jeziorski, Eric, Fieschi, Claire, Vogt, Guillaume, Donadieu, Jean, Pasquet, Marlène, Vasconcelos, Julia, Ardeniz, Fatma Omur, Martínez-Gallo, Mónica, Campos, Regis A., Jobim, Luiz Fernando, Martínez-Barricarte, Rubén, Liu, Kang, Cobat, Aurélie, Abel, Laurent, Casanova, Jean-Laurent, Bustamante, Jacinta
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2021; Springer Nature B.V; Springer Verlag
• Subjects: Adolescent; Adult; Age; Alleles; Biomedical and Life Sciences; Biomedicine; Cell Line; Child; Databases, Genetic; Disease; DNA Mutational Analysis; Female; GATA2 Deficiency; GATA2 Deficiency - diagnosis; GATA2 Deficiency - epidemiology; GATA2 Deficiency - genetics; Genes, Dominant; Genetic Association Studies; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Haploinsufficiency; Hematologic Diseases; Hematologic Diseases - diagnosis; Hematologic Diseases - etiology; Humans; Immunology; Infectious Diseases; Internal Medicine; Kaplan-Meier Estimate; Life Sciences; Male; Medical Microbiology; Middle Aged; Mutation; Mycobacterium Infections; Mycobacterium Infections - diagnosis; Mycobacterium Infections - etiology; Myelodysplastic syndrome; Original Article; Outcome Assessment, Health Care; Pedigree; Penetrance; Phenotype; Phenotypes; Whole Exome Sequencing; Young Adult; haploinsufficiency; GATA2; mycobacteria; tuberculosis; Primary immunodeficiency
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-020-00930-3

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.