Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

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 immuno...

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Detalles Bibliográficos
Autores: 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, Aróstegui JI
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p15122
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15122
Access Level:acceso abierto
Palabra clave:Postzygotic variants
gene mosaicism
primary immunodeficiency diseases
next-generation sequencing
amplicon-based deep sequencing
autoinflammatory diseases
Descripción
Sumario: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.

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