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

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; Nora Hilda Segura Méndez; Patricia O'Farrill Romanillos; Tom Le Voyer; Anne Puel; Christine Bellanné-Chantelot; Kacy A Ramirez; Lazaro Lorenzo-Diaz; Noé Ramirez Alejo; Rebeca Pérez de Diego; 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; Jacinta Bustamante

doi:10.1007/s10875-020-00930-3

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

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

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, …

Journal of clinical immunology, Vol.41(3), pp.639-657

01/04/2021

DOI: https://doi.org/10.1007/s10875-020-00930-3

PMID: 33417088

Résumé

Adolescent

Adult

Alleles

Cell Line

Child

Databases, Genetic

DNA Mutational Analysis

Female

GATA2 Deficiency - diagnosis

GATA2 Deficiency - epidemiology

GATA2 Deficiency - genetics

Genes, Dominant

Genetic Association Studies - methods

Genetic Predisposition to Disease

Genotype

Germ-Line Mutation

Haploinsufficiency

Hematologic Diseases - diagnosis

Hematologic Diseases - etiology

Humans

Kaplan-Meier Estimate

Male

Middle Aged

Mycobacterium Infections - diagnosis

Mycobacterium Infections - etiology

Outcome Assessment, Health Care

Pedigree

Penetrance

Phenotype

Whole Exome Sequencing

Young Adult

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. We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. 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. 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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Détails

Titre: Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance
Créateurs - sans rôle: Carmen Oleaga-Quintas - Department of Immunology, School of Medicine, Complutense University, Madrid, Spain
Edgar Borges de Oliveira-Júnior - Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
Jérémie Rosain - University of Paris, Imagine Institute, Paris, France
Franck Rapaport - Rockefeller University
Caroline Deswarte - University of Paris, Imagine Institute, Paris, France
Antoine Guérin - University of Paris, Imagine Institute, Paris, France
Sairaj Munavar Sajjath - Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
Yu Jerry Zhou - Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
Stéphane Marot - Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France
Claire Lozano - Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France
Lidia Branco - Department of Immunology, Porto Hospital Center, Porto, Portugal
Nuria Fernández-Hidalgo - Service of Infectious Diseases, University Hospital Vall d'Hebron, Barcelona, Spain
Dukhee Betty Lew - The Children's Foundation Research Center and Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA
Anne-Sophie Brunel - Infectious Diseases Unit, Montpellier, France
Caroline Thomas - Pediatric Oncology and Hematology, University Hospital of Nantes, Nantes, France
Elise Launay - Pediatric Oncology and Hematology, University Hospital of Nantes, Nantes, France
Andrés Augusto Arias - School of Microbiology, University of Antioquia UdeA, Medellin, Colombia
Alexis Cuffel - Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France
Vanesa Cunill Monjo - Department of Immunology, Son Espases Hospital, Palma de Mallorca, Spain
Anna-Lena Neehus - University of Paris, Imagine Institute, Paris, France
Laura Marques - Department of Pediatrics, Porto Hospital Center, Porto, Portugal
Manon Roynard - University of Paris, Imagine Institute, Paris, France
Marcela Moncada-Vélez - Rockefeller University
Bengü Gerçeker - Department of Dermatology, Ege University Medical Faculty, İzmir, Turkey
Roger Colobran - Area of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain
Marie-Gabrielle Vigué - Infectious Diseases Unit, Montpellier, France
Gabriela Lopez-Herrera - Immunodeficiencies Research Unit at the National Institute of Pediatrics, Mexico City, Mexico
Laura Berron-Ruiz - Immunodeficiencies Research Unit at the National Institute of Pediatrics, Mexico City, Mexico
Nora Hilda Segura Méndez - Allergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico
Patricia O'Farrill Romanillos - Allergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico
Tom Le Voyer - University of Paris, Imagine Institute, Paris, France
Anne Puel - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
Christine Bellanné-Chantelot - Pitié-Salpêtrière Hospital
Kacy A Ramirez - LeBonheur Children's Hospital, West Patient Tower, Rm 433, Memphis, TN, 38103, USA
Lazaro Lorenzo-Diaz - University of Paris, Imagine Institute, Paris, France
Noé Ramirez Alejo - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
Rebeca Pérez de Diego - Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain
Antonio Condino-Neto - Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
Fethi Mellouli - National Center for Bone Marrow Grafts, Tunis Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
Carlos Rodriguez-Gallego - Department of Immunology, Gran Canaria Dr. Negrin University Hospital, Las Palmas de Gran Canaria, Spain
Torsten Witte - Clinic of Immunology and Rheumatology, Medical School of Hannover, Hannover, Germany
José Franco Restrepo - Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UdeA, Medellin, Colombia
Mariana Jobim - Department of Immunology, Clinicas Hospital of Porto Alegre, Porto Alegre, RS, Brazil
Stéphanie Boisson-Dupuis - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
Eric Jeziorski - Department of Pediatrics, Infectious Diseases and Immunology, CHU Montpellier, Montpellier, France
Claire Fieschi - Assistance Publique – Hôpitaux de Paris
Guillaume Vogt - University of Paris, Imagine Institute, Paris, France
Jean Donadieu - Assistance Publique – Hôpitaux de Paris
Marlène Pasquet - Center of Research in Cancerology, INSERM U1037, Team 16, IUCT-Oncopole, Toulouse, France
Julia Vasconcelos - Department of Immunology, Porto Hospital Center, Porto, Portugal
Fatma Omur Ardeniz - Internal Medicine Allergy and Clinical Immunology, Medical School of Ege, Izmir, Turkey
Mónica Martínez-Gallo - Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
Regis A Campos - Department of Allergy and Clinical Immunology, Medical School, Federal University of Bahia, Salvador, BA, Brazil
Luiz Fernando Jobim - Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
Rubén Martínez-Barricarte - Rockefeller University
Kang Liu - Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
Aurélie Cobat - University of Paris, Imagine Institute, Paris, France
Laurent Abel - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
Jean-Laurent Casanova - Howard Hughes Medical Institute, New York, NY, USA
Jacinta Bustamante - Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr
Détails de publication: Journal of clinical immunology, Vol.41(3), pp.639-657
Note de subvention: R37 AI095983 / NIAID NIH HHS R37AI095983 / NIH HHS R01 AI095983 / NIAID NIH HHS
Identifiants: 99148084809311
Unité académique: Pathogenesis and Control of Chronic and Emerging Infections - PCCEI
Langue: English
Type de ressource: Journal article