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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| Format: | Article |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02503/full |
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| author | Susana L. Silva Susana L. Silva Susana L. Silva Mariana Fonseca Mariana Fonseca Marcelo L. M. Pereira Sara P. Silva Sara P. Silva Sara P. Silva Rita R. Barbosa Ana Serra-Caetano Ana Serra-Caetano Elena Blanco Elena Blanco Pedro Rosmaninho Pedro Rosmaninho Martin Pérez-Andrés Martin Pérez-Andrés Ana Berta Sousa Ana Berta Sousa Ana Berta Sousa Alexandre A. S. F. Raposo Alexandre A. S. F. Raposo Margarida Gama-Carvalho Rui M. M. Victorino Rui M. M. Victorino Rui M. M. Victorino Lennart Hammarstrom Ana E. Sousa Ana E. Sousa |
| author_facet | Susana L. Silva Susana L. Silva Susana L. Silva Mariana Fonseca Mariana Fonseca Marcelo L. M. Pereira Sara P. Silva Sara P. Silva Sara P. Silva Rita R. Barbosa Ana Serra-Caetano Ana Serra-Caetano Elena Blanco Elena Blanco Pedro Rosmaninho Pedro Rosmaninho Martin Pérez-Andrés Martin Pérez-Andrés Ana Berta Sousa Ana Berta Sousa Ana Berta Sousa Alexandre A. S. F. Raposo Alexandre A. S. F. Raposo Margarida Gama-Carvalho Rui M. M. Victorino Rui M. M. Victorino Rui M. M. Victorino Lennart Hammarstrom Ana E. Sousa Ana E. Sousa |
| author_sort | Susana L. Silva |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T06:24:01Z |
| format | Article |
| id | doaj.art-f08925a14492451396341b37449e3910 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T06:24:01Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f08925a14492451396341b37449e39102022-12-21T17:57:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02503479182Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic BurdenSusana L. Silva0Susana L. Silva1Susana L. Silva2Mariana Fonseca3Mariana Fonseca4Marcelo L. M. Pereira5Sara P. Silva6Sara P. Silva7Sara P. Silva8Rita R. Barbosa9Ana Serra-Caetano10Ana Serra-Caetano11Elena Blanco12Elena Blanco13Pedro Rosmaninho14Pedro Rosmaninho15Martin Pérez-Andrés16Martin Pérez-Andrés17Ana Berta Sousa18Ana Berta Sousa19Ana Berta Sousa20Alexandre A. S. F. Raposo21Alexandre A. S. F. Raposo22Margarida Gama-Carvalho23Rui M. M. Victorino24Rui M. M. Victorino25Rui M. M. Victorino26Lennart Hammarstrom27Ana E. Sousa28Ana E. Sousa29Faculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalCentro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalFaculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalCentro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalDepartment of Medicine, Cancer Research Centre (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca (USAL), Salamanca, SpainBiomedical Research Networking Centre on Cancer-CIBER-CIBERONC, Number CB16/12/00400, Institute of Health Carlos III, Madrid, SpainFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalDepartment of Medicine, Cancer Research Centre (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca (USAL), Salamanca, SpainBiomedical Research Networking Centre on Cancer-CIBER-CIBERONC, Number CB16/12/00400, Institute of Health Carlos III, Madrid, SpainFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalCentro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalFaculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Lisbon, PortugalFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalCentro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, PortugalDepartment of Laboratory Medicine, Karolinska Institutet, Stockholm, SwedenFaculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, PortugalCentro de Imunodeficiências Primárias, Centro Académico de Medicina de Lisboa, Centro Hospitalar Universitário Lisboa Norte and Faculdade de Medicina da Universidade de Lisboa and Instituto de Medicina Molecular, Lisbon, PortugalMonozygotic 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02503/fullCVIDflow-cytometrypolygenic diseasegeneticsWESmonozygotic twins |
| spellingShingle | Susana L. Silva Susana L. Silva Susana L. Silva Mariana Fonseca Mariana Fonseca Marcelo L. M. Pereira Sara P. Silva Sara P. Silva Sara P. Silva Rita R. Barbosa Ana Serra-Caetano Ana Serra-Caetano Elena Blanco Elena Blanco Pedro Rosmaninho Pedro Rosmaninho Martin Pérez-Andrés Martin Pérez-Andrés Ana Berta Sousa Ana Berta Sousa Ana Berta Sousa Alexandre A. S. F. Raposo Alexandre A. S. F. Raposo Margarida Gama-Carvalho Rui M. M. Victorino Rui M. M. Victorino Rui M. M. Victorino Lennart Hammarstrom Ana E. Sousa Ana E. Sousa Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden Frontiers in Immunology CVID flow-cytometry polygenic disease genetics WES monozygotic twins |
| 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 | CVID flow-cytometry polygenic disease genetics WES monozygotic twins |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02503/full |
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