Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases
Por:
Mensa-Vilaró A, Bravo M, de la Calle-Martin O, Franco-Jarava C, Martínez-Saavedra MT, González-Granado LI, González-Roca E, Fuster JL, Alsina L, Mutchinick OM, Balderrama-Rodríguez A, Ramos E, Modesto C, Mesa-Del-Castillo P, Ortego-Centeno N, Clemente D, Souto A, Palmou N, Remesal A, Leslie KS, Gómez de la Fuente E, Bravo Gallego LY, Campistol JM, Dhouib NG, Bejaoui M, Dutra LA, Terreri MT, Mosquera C, González T, Cañellas J, García-Ruiz de Morales JM, Wouters CH, Bosque MT, Cham WT, Jiménez-Treviño S, de Inocencio J, Bloomfield M, Pérez de Diego R, Martínez-Pomar N, Rodríguez-Pena R, González-Santesteban C, Soler-Palacín P, Casals F, Yagüe J, Allende LM, Rodríguez-Gallego JC, Colobran R, Martínez-Martínez L, López-Granados E and Aróstegui JI
Publicada:
1 ene 2019
Ahead of Print:
29 sep 2018
Resumen:
Background: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed.
Objective: We sought to investigate the incidence of gene mosaicism in patients with PIDs.
Methods: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics.
Results: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderateto- high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time.
Conclusion: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.
Filiaciones:
Mensa-Vilaró A:
Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain
Bravo M:
Department of Immunology, Hospital Universitario La Paz, Madrid, Spain
de la Calle-Martin O:
Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Franco-Jarava C:
Department of Immunology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Martínez-Saavedra MT:
Department of Immunology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
González-Granado LI:
Primary Immunodeficiencies Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain
Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
Universidad Complutense, Madrid, Spain
González-Roca E:
Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain
Fuster JL:
Department of Hematology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
Alsina L:
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues, Spain
Department of Allergy and Clinical Immunology, Hospital Sant Joan de Deu, Esplugues, Spain
Mutchinick OM:
Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
Balderrama-Rodríguez A:
Jurisdicción Sanitaria Cuajimalpa, Servicios de Salud Pública del Distrito Federal, México
Ramos E:
Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain
Modesto C:
Department of Pediatric Rheumatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Mesa-Del-Castillo P:
Department of Pediatric Rheumatology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
Ortego-Centeno N:
Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain
Clemente D:
Department of Pediatric Rheumatology, Hospital Universitario Niño Jesús, Madrid, Spain
Souto A:
Department of Rheumatology, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
Palmou N:
Department of Rheumatology, Hospital Universitario Marques de Valdecilla, Santander, Spain
Remesal A:
Department of Pediatric Rheumatology, Hospital Universitario La Paz, Madrid, Spain
Leslie KS:
Department of Dermatology, University of California San Francisco, San Francisco USA
Gómez de la Fuente E:
Department of Dermatology, Hospital Universitario Fundacion Alcorcon, Alcorcon, Spain
Bravo Gallego LY:
Department of Immunology, Hospital Universitario La Paz, Madrid, Spain
Campistol JM:
Department of Nephrology, Hospital Clínic-IDIBAPS, Barcelona, Spain
Dhouib NG:
Pediatric Immuno-Hematology Unit, Bone Marrow Transplantation Center, Tunis, Tunisia
Bejaoui M:
Pediatric Immuno-Hematology Unit, Bone Marrow Transplantation Center, Tunis, Tunisia
Dutra LA:
Division of General Neurology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
Terreri MT:
Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
Mosquera C:
Department of Pediatric Rheumatology, Universidad El Bosque, Bogotá, Colombia
González T:
Department of Pediatric Rheumatology, Universidad de Cartagena, Cartagena, Colombia
Cañellas J:
Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
García-Ruiz de Morales JM:
Department of Immunology, Complejo Asistencial Universitario de Leon, Leon, Spain
Wouters CH:
Departments of Pediatric Rheumatology, Microbiology and Immunology, University Hospitals Leuven, KU University of Leuven, Leuven, Belgium
Bosque MT:
Department of Rheumatology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain
Cham WT:
Department of Pediatric Rheumatology, Sunway Medical Centre, Kuala Lumpur, Malaysia
Jiménez-Treviño S:
Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain
de Inocencio J:
Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
Department of Pediatric Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain
Bloomfield M:
Department of Immunology, 2(nd) Faculty of Medicine, Charles University and University Hospital in Motol, Prague, Czech Republic
Pérez de Diego R:
Laboratory of Immunogenetics of Diseases, IdiPAZ Institute for Health Research, Hospital Universitario La Paz, Madrid, Spain
Innate Immunity Group, IdiPAZ Institute for Health Research, Hospital Universitario La Paz, Madrid, Spain
Martínez-Pomar N:
Department of Immunology, Hospital Universitario Son Espases, Palma de Mallorca, Spain
Rodríguez-Pena R:
Department of Immunology, Hospital Universitario La Paz, Madrid, Spain
González-Santesteban C:
Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Soler-Palacín P:
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain
Casals F:
Department of Genomics, Universitat Pompeu Fabra, Barcelona, Spain
Yagüe J:
Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain
Allende LM:
Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
Universidad Complutense, Madrid, Spain
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
Rodríguez-Gallego JC:
Department of Immunology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
Colobran R:
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Immunology Division, Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain
Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain
Martínez-Martínez L:
Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
López-Granados E:
Department of Immunology, Hospital Universitario La Paz, Madrid, Spain
Aróstegui JI:
Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain
Green Submitted, Green Accepted
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