RT Journal Article
T1 Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.
A1 Mensa-Vilaró, Anna
A1 Bravo García-Morato, María
A1 de la Calle-Martin, Oscar
A1 Franco-Jarava, Clara
A1 Martínez-Saavedra, María Teresa
A1 González-Granado, Luis I
A1 González-Roca, Eva
A1 Fuster, Jose Luis
A1 Alsina, Laia
A1 Mutchinick, Osvaldo M
A1 Balderrama-Rodríguez, Angélica
A1 Ramos, Eduardo
A1 Modesto, Consuelo
A1 Mesa-Del-Castillo, Pablo
A1 Ortego-Centeno, Norberto
A1 Clemente, Daniel
A1 Souto, Alejandro
A1 Palmou, Natalia
A1 Remesal, Agustín
A1 Leslie, Kieron S
A1 Gómez de la Fuente, Enrique
A1 Yadira Bravo Gallego, Luz
A1 Campistol, Josep María
A1 Dhouib, Naouel Guirat
A1 Bejaoui, Mohamed
A1 Dutra, Lívia Almeida
A1 Terreri, Maria Teresa
A1 Mosquera, Catalina
A1 González, Tatiana
A1 Cañellas, Jerónima
A1 García-Ruiz de Morales, José María
A1 Wouters, Carine H
A1 Bosque, María Teresa
A1 Cham, Weng Tarng
A1 Jiménez-Treviño, Santiago
A1 de Inocencio, Jaime
A1 Bloomfield, Markéta
A1 Pérez de Diego, Rebeca
A1 Martínez-Pomar, Natalia
A1 Rodríguez-Pena, Rebeca
A1 González-Santesteban, Cecilia
A1 Soler-Palacín, Pere
A1 Casals, Ferran
A1 Yagüe, Jordi
A1 Allende, Luis M
A1 Rodríguez-Gallego, José Carlos
A1 Colobran, Roger
A1 Martínez-Martínez, Laura
A1 López-Granados, Eduardo
A1 Aróstegui, Juan I
K1 Postzygotic variants
K1 amplicon-based deep sequencing
K1 autoinflammatory diseases
K1 gene mosaicism
K1 next-generation sequencing
K1 primary immunodeficiency diseases
AB 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. We sought to investigate the incidence of gene mosaicism in patients with PIDs. 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. 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. 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.
YR 2018
FD 2018-09-29
LK http://hdl.handle.net/10668/13014
UL http://hdl.handle.net/10668/13014
LA en
DS RISalud
RD Apr 6, 2025