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Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience
CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668901/ https://www.ncbi.nlm.nih.gov/pubmed/36405754 http://dx.doi.org/10.3389/fimmu.2022.1020927 |
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author | Urdinez, Luciano Erra, Lorenzo Palma, Alejandro M. Mercogliano, María F. Fernandez, Julieta Belén Prieto, Emma Goris, Verónica Bernasconi, Andrea Sanz, Marianela Villa, Mariana Bouso, Carolina Caputi, Lucia Quesada, Belen Solis, Daniel Aguirre Bruzzo, Anabel Katsicas, Maria Martha Galluzzo, Laura Weyersberg, Christian Bocian, Marcela Bujan, Maria Marta Oleastro, Matías Almejun, María B. Danielian, Silvia |
author_facet | Urdinez, Luciano Erra, Lorenzo Palma, Alejandro M. Mercogliano, María F. Fernandez, Julieta Belén Prieto, Emma Goris, Verónica Bernasconi, Andrea Sanz, Marianela Villa, Mariana Bouso, Carolina Caputi, Lucia Quesada, Belen Solis, Daniel Aguirre Bruzzo, Anabel Katsicas, Maria Martha Galluzzo, Laura Weyersberg, Christian Bocian, Marcela Bujan, Maria Marta Oleastro, Matías Almejun, María B. Danielian, Silvia |
author_sort | Urdinez, Luciano |
collection | PubMed |
description | CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described. |
format | Online Article Text |
id | pubmed-9668901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96689012022-11-18 Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience Urdinez, Luciano Erra, Lorenzo Palma, Alejandro M. Mercogliano, María F. Fernandez, Julieta Belén Prieto, Emma Goris, Verónica Bernasconi, Andrea Sanz, Marianela Villa, Mariana Bouso, Carolina Caputi, Lucia Quesada, Belen Solis, Daniel Aguirre Bruzzo, Anabel Katsicas, Maria Martha Galluzzo, Laura Weyersberg, Christian Bocian, Marcela Bujan, Maria Marta Oleastro, Matías Almejun, María B. Danielian, Silvia Front Immunol Immunology CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9668901/ /pubmed/36405754 http://dx.doi.org/10.3389/fimmu.2022.1020927 Text en Copyright © 2022 Urdinez, Erra, Palma, Mercogliano, Fernandez, Prieto, Goris, Bernasconi, Sanz, Villa, Bouso, Caputi, Quesada, Solis, Aguirre Bruzzo, Katsicas, Galluzzo, Weyersberg, Bocian, Bujan, Oleastro, Almejun and Danielian https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Urdinez, Luciano Erra, Lorenzo Palma, Alejandro M. Mercogliano, María F. Fernandez, Julieta Belén Prieto, Emma Goris, Verónica Bernasconi, Andrea Sanz, Marianela Villa, Mariana Bouso, Carolina Caputi, Lucia Quesada, Belen Solis, Daniel Aguirre Bruzzo, Anabel Katsicas, Maria Martha Galluzzo, Laura Weyersberg, Christian Bocian, Marcela Bujan, Maria Marta Oleastro, Matías Almejun, María B. Danielian, Silvia Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title | Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title_full | Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title_fullStr | Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title_full_unstemmed | Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title_short | Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience |
title_sort | expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous card11-associated diseases: a single center experience |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668901/ https://www.ncbi.nlm.nih.gov/pubmed/36405754 http://dx.doi.org/10.3389/fimmu.2022.1020927 |
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