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

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. Keywords: GATA2; Primary immunodeficiency; haploinsufficiency; mycobacteria; tuberculosis.

• Autores: Moncada Vélez, Marcela; Arias Sierra, Andrés Augusto; Franco Restrepo, José Luis; Oleaga Quintas, Carmen; Borges de Oliveira Júnior, Edgar; Rosain, Jérémie; Rapaport, Franck; Deswarte, Caroline; Guérin, Antoine; Munavar Sajjath, Sairaj; Zhou, Yu Jerry; Marot, Stéphane; Lozano, Claire; Branco, Lidia; Fernández Hidalgo, Nuria; Lew Dukhee, Betty; Brunel, Anne Sophie; Launay, Elise; Thomas, Caroline; Cuffel, Alexis; Cunill Monjo, Vanesa; Neehus, Anna Lena; Marques, Laura; Roynard, Manon; Gerçeker, Bengü; Colobran, Roger; Vigué, Marie Gabrielle; López Herrera, Gabriela; Berron Ruiz, Laura; Segura Méndez, Nora Hilda; O'Farrill Romanillos, Patricia; Le Voyer, Tom; Puel, Anne; Bellanné Chantelot, Christine; Ramirez, Kacy A; Lorenzo Díaz, Lazaro; Ramirez Alejo, Noé; Pérez de Diego, Rebeca; Condino Neto, Antonio; Mellouli, Fethi; Rodríguez Gallego, Carlos; Witte, Torsten; 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
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2021
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/40495
• Acceso en línea: https://hdl.handle.net/10495/40495
• Palabra clave: Alleles; Alelos; DNA Mutational Analysis; Análisis Mutacional de ADN; Databases, Genetic; Bases de Datos Genéticas; Exome Sequencing; Secuenciación del Exoma; GATA2 Deficiency; Deficiencia GATA2; Genes, Dominant; Genes Dominantes; Genetic Association Studies; Estudios de Asociación Genética; Genetic Predisposition to Disease; Predisposición Genética a la Enfermedad; Genotype; Genotipo; Germ-Line Mutation; Mutación de Línea Germinal; Haploinsufficiency; Haploinsuficiencia; Hematologic Diseases; Enfermedades Hematológicas; Kaplan-Meier Estimate; Estimación de Kaplan-Meier; Mycobacterium Infections; Infecciones por Mycobacterium; Outcome Assessment, Health Care; Evaluación de Resultado en la Atención de Salud; Penetrance; Penetrancia; Phenotype; Fenotipo; https://id.nlm.nih.gov/mesh/D010641; https://id.nlm.nih.gov/mesh/D000483; https://id.nlm.nih.gov/mesh/D004252; https://id.nlm.nih.gov/mesh/D030541; https://id.nlm.nih.gov/mesh/D000073359; https://id.nlm.nih.gov/mesh/D000077428; https://id.nlm.nih.gov/mesh/D005799; https://id.nlm.nih.gov/mesh/D056726; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D005838; https://id.nlm.nih.gov/mesh/D018095; https://id.nlm.nih.gov/mesh/D057895; https://id.nlm.nih.gov/mesh/D006402; https://id.nlm.nih.gov/mesh/D053208; https://id.nlm.nih.gov/mesh/D009164; https://id.nlm.nih.gov/mesh/D017063; https://id.nlm.nih.gov/mesh/D019683
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/