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Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden

Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and...

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Autores principales: Silva, Susana L., Fonseca, Mariana, Pereira, Marcelo L. M., Silva, Sara P., Barbosa, Rita R., Serra-Caetano, Ana, Blanco, Elena, Rosmaninho, Pedro, Pérez-Andrés, Martin, Sousa, Ana Berta, Raposo, Alexandre A. S. F., Gama-Carvalho, Margarida, Victorino, Rui M. M., Hammarstrom, Lennart, Sousa, Ana E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882918/
https://www.ncbi.nlm.nih.gov/pubmed/31824477
http://dx.doi.org/10.3389/fimmu.2019.02503
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author Silva, Susana L.
Fonseca, Mariana
Pereira, Marcelo L. M.
Silva, Sara P.
Barbosa, Rita R.
Serra-Caetano, Ana
Blanco, Elena
Rosmaninho, Pedro
Pérez-Andrés, Martin
Sousa, Ana Berta
Raposo, Alexandre A. S. F.
Gama-Carvalho, Margarida
Victorino, Rui M. M.
Hammarstrom, Lennart
Sousa, Ana E.
author_facet Silva, Susana L.
Fonseca, Mariana
Pereira, Marcelo L. M.
Silva, Sara P.
Barbosa, Rita R.
Serra-Caetano, Ana
Blanco, Elena
Rosmaninho, Pedro
Pérez-Andrés, Martin
Sousa, Ana Berta
Raposo, Alexandre A. S. F.
Gama-Carvalho, Margarida
Victorino, Rui M. M.
Hammarstrom, Lennart
Sousa, Ana E.
author_sort Silva, Susana L.
collection PubMed
description Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies.
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spelling pubmed-68829182019-12-10 Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden Silva, Susana L. Fonseca, Mariana Pereira, Marcelo L. M. Silva, Sara P. Barbosa, Rita R. Serra-Caetano, Ana Blanco, Elena Rosmaninho, Pedro Pérez-Andrés, Martin Sousa, Ana Berta Raposo, Alexandre A. S. F. Gama-Carvalho, Margarida Victorino, Rui M. M. Hammarstrom, Lennart Sousa, Ana E. Front Immunol Immunology Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies. Frontiers Media S.A. 2019-11-22 /pmc/articles/PMC6882918/ /pubmed/31824477 http://dx.doi.org/10.3389/fimmu.2019.02503 Text en Copyright © 2019 Silva, Fonseca, Pereira, Silva, Barbosa, Serra-Caetano, Blanco, Rosmaninho, Pérez-Andrés, Sousa, Raposo, Gama-Carvalho, Victorino, Hammarstrom and Sousa. http://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
Silva, Susana L.
Fonseca, Mariana
Pereira, Marcelo L. M.
Silva, Sara P.
Barbosa, Rita R.
Serra-Caetano, Ana
Blanco, Elena
Rosmaninho, Pedro
Pérez-Andrés, Martin
Sousa, Ana Berta
Raposo, Alexandre A. S. F.
Gama-Carvalho, Margarida
Victorino, Rui M. M.
Hammarstrom, Lennart
Sousa, Ana E.
Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title_full Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title_fullStr Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title_full_unstemmed Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title_short Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden
title_sort monozygotic twins concordant for common variable immunodeficiency: strikingly similar clinical and immune profile associated with a polygenic burden
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882918/
https://www.ncbi.nlm.nih.gov/pubmed/31824477
http://dx.doi.org/10.3389/fimmu.2019.02503
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