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Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases
A. Mensa-Vilaró, M. Bravo García-Morato, O. de la Calle-Martin, C. Franco-Jarava, MT. Martínez-Saavedra, LI. González-Granado, E. González-Roca, JL. Fuster, L. Alsina, OM. Mutchinick, A. Balderrama-Rodríguez, E. Ramos, C. Modesto, P....
Language English Country United States
Document type Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Alleles * MeSH
- Gene Frequency * MeSH
- Humans MeSH
- Mosaicism * MeSH
- Family MeSH
- Immunologic Deficiency Syndromes genetics immunology MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial MeSH
- Research Support, Non-U.S. Gov't MeSH
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 moderate-to-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.
Department of Allergy and Clinical Immunology Hospital Sant Joan de Deu Esplugues Spain
Department of Dermatology Hospital Universitario Fundacion Alcorcon Alcorcon Spain
Department of Dermatology University of California San Francisco San Francisco Calif
Department of Genomics Universitat Pompeu Fabra Barcelona Spain
Department of Hematology Hospital Clínico Universitario Virgen de la Arrixaca Murcia Spain
Department of Immunology CDB Hospital Clínic IDIBAPS Barcelona Spain
Department of Immunology Complejo Asistencial Universitario de Leon Leon Spain
Department of Immunology Hospital de la Santa Creu i Sant Pau Barcelona Spain
Department of Immunology Hospital Universitario 12 de Octubre Madrid Spain
Department of Immunology Hospital Universitario La Paz Madrid Spain
Department of Immunology Hospital Universitario Son Espases Palma de Mallorca Spain
Department of Internal Medicine Hospital Universitario San Cecilio Granada Spain
Department of Nephrology Hospital Clínic IDIBAPS Barcelona Spain
Department of Pediatric Rheumatology Hospital Universitari Vall d'Hebron Barcelona Spain
Department of Pediatric Rheumatology Hospital Universitario 12 de Octubre Madrid Spain
Department of Pediatric Rheumatology Hospital Universitario La Paz Madrid Spain
Department of Pediatric Rheumatology Hospital Universitario Niño Jesús Madrid Spain
Department of Pediatric Rheumatology Sunway Medical Centre Kuala Lumpur Malaysia
Department of Pediatric Rheumatology Universidad de Cartagena Cartagena Colombia
Department of Pediatric Rheumatology Universidad El Bosque Bogota Colombia
Department of Pediatrics Hospital Universitario Central de Asturias Oviedo Spain
Department of Rheumatology Hospital Clinico Universitario de Santiago Santiago de Compostela Spain
Department of Rheumatology Hospital Clinico Universitario Lozano Blesa Zaragoza Spain
Department of Rheumatology Hospital Universitari Germans Trias i Pujol Badalona Spain
Department of Rheumatology Hospital Universitario Marques de Valdecilla Santander Spain
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu Esplugues Spain
Instituto de Investigación i 12 Hospital Universitario 12 de Octubre Madrid Spain
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies Barcelona Spain
Jurisdicción Sanitaria Cuajimalpa Servicios de Salud Pública del Distrito Federal Mexico City Mexico
Pediatric Immuno Hematology Unit Bone Marrow Transplantation Center Tunis Tunisia
References provided by Crossref.org
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- $a Mensa-Vilaró, Anna $u Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain. Electronic address: amensa@clinic.ub.es.
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- $a Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases / $c A. Mensa-Vilaró, M. Bravo García-Morato, O. de la Calle-Martin, C. Franco-Jarava, MT. Martínez-Saavedra, LI. González-Granado, E. González-Roca, JL. Fuster, L. Alsina, OM. Mutchinick, A. Balderrama-Rodríguez, E. Ramos, C. Modesto, P. Mesa-Del-Castillo, N. Ortego-Centeno, D. Clemente, A. Souto, N. Palmou, A. Remesal, KS. Leslie, E. Gómez de la Fuente, L. Yadira Bravo Gallego, JM. Campistol, NG. Dhouib, M. Bejaoui, LA. Dutra, MT. Terreri, C. Mosquera, T. González, J. Cañellas, JM. García-Ruiz de Morales, CH. Wouters, MT. Bosque, WT. Cham, S. Jiménez-Treviño, J. de Inocencio, M. Bloomfield, R. Pérez de Diego, N. Martínez-Pomar, R. Rodríguez-Pena, C. González-Santesteban, P. Soler-Palacín, F. Casals, J. Yagüe, LM. Allende, JC. Rodríguez-Gallego, R. Colobran, L. Martínez-Martínez, E. López-Granados, JI. Aróstegui,
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- $a 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 moderate-to-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.
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