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

Anna Mensa-Vilaró, María Bravo García-Morato, Oscar de la Calle-Martin, Clara Franco-Jarava, María Teresa Martínez-Saavedra, Luis I González-Granado, Eva González-Roca, Jose Luis 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, Agustín Remesal, Kieron S Leslie, Enrique Gómez de la Fuente, Luz Yadira Bravo Gallego, Josep María Campistol, Naouel Guirat Dhouib, Mohamed Bejaoui, Lívia Almeida Dutra, Maria Teresa Terreri, Catalina Mosquera, Tatiana González, Jerónima Cañellas, José María García-Ruiz de Morales, Carine H Wouters, María Teresa Bosque, Weng Tarng Cham, Santiago Jiménez-Treviño, Jaime de Inocencio, Markéta Bloomfield, Rebeca Pérez de Diego, Natalia Martínez-Pomar, Rebeca Rodríguez-Pena, Cecilia González-Santesteban, Pere Soler-Palacín, Ferran Casals, Jordi Yagüe, Luis M Allende, José Carlos Rodríguez-Gallego, Roger Colobran, Laura Martínez-Martínez, Eduardo López-Granados, Juan I Aróstegui

Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are called somatic, gonadal and gonosomal mosaicism, which differ on the body distribution of post-zygotic mutations. Mosaicism has been occasionally reported in primary immunodeficiency diseases (PID) since early 90s, but its real involvement has not been systematically addressed. To investigate the incidence of gene mosaicism in PID. The amplicon-based deep sequencing method was employed in the three parts of the study that establish the allele frequency of germline variants (n:100), the incidence of parental gonosomal mosaicism in PID families with de novo mutations (n:92) and the incidence of mosaicism in PID families with moderate-to-high suspicious (n:36), respectively. Additional investigations evaluated body distribution of post-zygotic mutations, their stability over time and their characteristics. The range of allele frequency 44.1-55.6% was established for germline variants. Those with minor allele frequency (MAF) <44.1% were assumed as post-zygotic. Mosaicism was detected in 30/128 (23.4%) PID families, with variable MAF (0.8-40.5%). Parental gonosomal mosaicism was detected in 6/92 (6.5%) families with de novo mutations, whereas a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicious. In most analyzed cases, mosaicism was found both uniformly distributed and stable over time. This study represents the largest one performed to date to investigate mosaicism in PID, revealing that it affects ≈25% of enrolled families. Our results may have serious consequences regarding patients' treatment and genetic counseling, and reinforce the use of NGS-based methods in the routine analyses of PID.