Anna Mensa-Vilaró1, María Bravo García-Morato2, Oscar de la Calle-Martin3, Clara Franco-Jarava4, María Teresa Martínez-Saavedra5, Luis I González-Granado6, Eva González-Roca7, Jose Luis Fuster8, Laia Alsina9, Osvaldo M Mutchinick10, Angélica Balderrama-Rodríguez11, Eduardo Ramos12, Consuelo Modesto13, Pablo Mesa-Del-Castillo14, Norberto Ortego-Centeno15, Daniel Clemente16, Alejandro Souto17, Natalia Palmou18, Agustín Remesal19, Kieron S Leslie20, Enrique Gómez de la Fuente21, Luz Yadira Bravo Gallego2, Josep María Campistol22, Naouel Guirat Dhouib23, Mohamed Bejaoui23, Lívia Almeida Dutra24, Maria Teresa Terreri25, Catalina Mosquera26, Tatiana González27, Jerónima Cañellas28, José María García-Ruiz de Morales29, Carine H Wouters30, María Teresa Bosque31, Weng Tarng Cham32, Santiago Jiménez-Treviño12, Jaime de Inocencio33, Markéta Bloomfield34, Rebeca Pérez de Diego35, Natalia Martínez-Pomar36, Rebeca Rodríguez-Pena2, Cecilia González-Santesteban3, Pere Soler-Palacín37, Ferran Casals38, Jordi Yagüe7, Luis M Allende39, José Carlos Rodríguez-Gallego5, Roger Colobran40, Laura Martínez-Martínez3, Eduardo López-Granados2, Juan I Aróstegui41. 1. Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain. Electronic address: amensa@clinic.ub.es. 2. Department of Immunology, Hospital Universitario La Paz, Madrid, Spain. 3. Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 4. Department of Immunology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain. 5. Department of Immunology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain. 6. Primary Immunodeficiencies Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain; Universidad Complutense, Madrid, Spain. 7. Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain. 8. Department of Hematology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. 9. Department of Allergy and Clinical Immunology, Hospital Sant Joan de Deu, Esplugues, Spain; Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues, Spain. 10. Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. 11. Jurisdicción Sanitaria Cuajimalpa, Servicios de Salud Pública del Distrito Federal, Mexico City, Mexico. 12. Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain. 13. Department of Pediatric Rheumatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 14. Department of Pediatric Rheumatology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. 15. Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain. 16. Department of Pediatric Rheumatology, Hospital Universitario Niño Jesús, Madrid, Spain. 17. Department of Rheumatology, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. 18. Department of Rheumatology, Hospital Universitario Marques de Valdecilla, Santander, Spain. 19. Department of Pediatric Rheumatology, Hospital Universitario La Paz, Madrid, Spain. 20. Department of Dermatology, University of California San Francisco, San Francisco, Calif. 21. Department of Dermatology, Hospital Universitario Fundacion Alcorcon, Alcorcon, Spain. 22. Department of Nephrology, Hospital Clínic-IDIBAPS, Barcelona, Spain. 23. Pediatric Immuno-Hematology Unit, Bone Marrow Transplantation Center, Tunis, Tunisia. 24. Division of General Neurology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. 25. Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. 26. Department of Pediatric Rheumatology, Universidad El Bosque, Bogota, Colombia. 27. Department of Pediatric Rheumatology, Universidad de Cartagena, Cartagena, Colombia. 28. Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 29. Department of Immunology, Complejo Asistencial Universitario de Leon, Leon, Spain. 30. Departments of Pediatric Rheumatology, Microbiology and Immunology, University Hospitals Leuven, KU University of Leuven, Leuven, Belgium. 31. Department of Rheumatology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain. 32. Department of Pediatric Rheumatology, Sunway Medical Centre, Kuala Lumpur, Malaysia. 33. Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain; Department of Pediatric Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain. 34. Department of Immunology, 2(nd) Faculty of Medicine, Charles University and University Hospital in Motol, Prague, Czech Republic. 35. Laboratory of Immunogenetics of Diseases, IdiPAZ Institute for Health Research, Hospital Universitario La Paz, Madrid, Spain; Innate Immunity Group, IdiPAZ Institute for Health Research, Hospital Universitario La Paz, Madrid, Spain. 36. Department of Immunology, Hospital Universitario Son Espases, Palma de Mallorca, Spain. 37. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain; Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain. 38. Department of Genomics, Universitat Pompeu Fabra, Barcelona, Spain. 39. Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain; Universidad Complutense, Madrid, Spain; Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. 40. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain; Immunology Division, Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain. 41. Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain. Electronic address: jiaroste@clinic.ub.es.
Abstract
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.
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.
Authors: Jahnavi Aluri; Alicia Bach; Saara Kaviany; Luana Chiquetto Paracatu; Maleewan Kitcharoensakkul; Magdalena A Walkiewicz; Christopher D Putnam; Marwan Shinawi; Nermina Saucier; Elise M Rizzi; Michael T Harmon; Molly P Keppel; Michelle Ritter; Morgan Similuk; Elaine Kulm; Michael Joyce; Adriana A de Jesus; Raphaela Goldbach-Mansky; Yi-Shan Lee; Marina Cella; Peggy L Kendall; Mary C Dinauer; Jeffrey J Bednarski; Christina Bemrich-Stolz; Scott W Canna; Shirley M Abraham; Matthew M Demczko; Jonathan Powell; Stacie M Jones; Amy M Scurlock; Suk See De Ravin; Jack J Bleesing; James A Connelly; V Koneti Rao; Laura G Schuettpelz; Megan A Cooper Journal: Blood Date: 2021-05-06 Impact factor: 25.476
Authors: David Buchbinder; Jolan E Walter; Manish J Butte; Wan-Yin Chan; Maria Chitty Lopez; Victoria R Dimitriades; Morna J Dorsey; Diane J Nugent; Jennifer M Puck; Jasjit Singh; Cathleen A Collins Journal: J Clin Immunol Date: 2021-01-07 Impact factor: 8.542
Authors: Jacques G Rivière; Clara Franco-Jarava; Mónica Martínez-Gallo; Aina Aguiló-Cucurull; Laura Blasco-Pérez; Ida Paramonov; María Antolín; Andrea Martín-Nalda; Pere Soler-Palacín; Roger Colobran Journal: Front Immunol Date: 2020-02-12 Impact factor: 7.561