Produção Nacional
Revisado por pares
Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases
2018; Elsevier BV; Volume: 143; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2018.09.009
ISSN1097-6825
AutoresAnna Mensa‐Vilaró, María Bravo García‐Morato, Oscar De La Calle-Martin, Clara Franco‐Jarava, María T. Martínez-Saavedra, Luis Ignacio González‐Granado, Eva González‐Roca, José Luís Fuster, Laia Alsina, Osvaldo M. Mutchinick, Angélica Balderrama-Rodríguez, Eduardo Ramos, Consuelo Modesto, Pablo Mesa-del-Castillo, Norberto Ortego‐Centeno, Daniel Clemente, Alejandro Souto, Natalia Palmou‐Fontana, Agustín Remesal, Kieron Leslie, Enrique Gómez de la Fuente, Luz Yadira Bravo‐Gallego, Josep M. Campistol, Naouel Guirat-Dhouib, Mohamed Béjaoui, Lívia Almeida Dutra, Maria Teresa Terreri, Catalina Mosquera, Tatiana González, Jerónima Cañellas, José María García-Ruiz de Morales, Carine Wouters, María Teresa Bosque, Weng Tarng Cham, Santiago Jiménez-Treviño, Jaime de Inocencio Arocena, Markéta Bloomfield, Rebeca Pérez de Diego, Natalia Martínez-Pomar, Rebeca Rodríguez‐Pena, Cecilia González‐Santesteban, Pere Soler‐Palacín, Ferrán Casals, Jordi Yagüe, Luis M. Allende, Carlos Rodríguez‐Gallego, Roger Colobrán, Laura Martínez‐Martínez, Eduardo López‐Granados, Juan I. Aróstegui,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoBackground 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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