Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19
Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months wh...
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1472957/full |
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| author | Renan Cesar Sbruzzi Renan Cesar Sbruzzi Mayara Jorgens Prado Bibiana Fam Bibiana Fam Helena Ashton Prolla Helena Ashton Prolla Alessandra Hellwig Grazielle Motta Rodrigues Fernanda de-Paris Mariana Jobim Osvaldo Artigalás Osvaldo Artigalás Yoann Seeleuthner Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jacinta Bustamante Jacinta Bustamante Jacinta Bustamante Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna |
| author_facet | Renan Cesar Sbruzzi Renan Cesar Sbruzzi Mayara Jorgens Prado Bibiana Fam Bibiana Fam Helena Ashton Prolla Helena Ashton Prolla Alessandra Hellwig Grazielle Motta Rodrigues Fernanda de-Paris Mariana Jobim Osvaldo Artigalás Osvaldo Artigalás Yoann Seeleuthner Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jacinta Bustamante Jacinta Bustamante Jacinta Bustamante Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna |
| author_sort | Renan Cesar Sbruzzi |
| collection | DOAJ |
| description | Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis. |
| format | Article |
| id | doaj-art-dcb4c401f5034adca5258e8807cf9031 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-dcb4c401f5034adca5258e8807cf90312024-11-13T04:39:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-11-011510.3389/fimmu.2024.14729571472957Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19Renan Cesar Sbruzzi0Renan Cesar Sbruzzi1Mayara Jorgens Prado2Bibiana Fam3Bibiana Fam4Helena Ashton Prolla5Helena Ashton Prolla6Alessandra Hellwig7Grazielle Motta Rodrigues8Fernanda de-Paris9Mariana Jobim10Osvaldo Artigalás11Osvaldo Artigalás12Yoann Seeleuthner13Jean-Laurent Casanova14Jean-Laurent Casanova15Jean-Laurent Casanova16Jean-Laurent Casanova17Jacinta Bustamante18Jacinta Bustamante19Jacinta Bustamante20Fernanda Sales Luiz Vianna21Fernanda Sales Luiz Vianna22Fernanda Sales Luiz Vianna23Fernanda Sales Luiz Vianna24Fernanda Sales Luiz Vianna25Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilGraduate program in Molecular and Cellular Biology, Department of Genetics and Molecular Biology – Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilLaboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilLaboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilGraduate program in Molecular and Cellular Biology, Department of Genetics and Molecular Biology – Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilLaboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilFaculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilLaboratory Diagnostic Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilLaboratory Diagnostic Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilLaboratory Diagnostic Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilTransplant Immunology and Personalized Medicine Unit, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilMedical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilGenomic Medicine Program, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, FranceLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, FranceSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States0Department of Pediatrics, Necker Hospital for Sick Children, Paris, France1Howard Hughes Medical Institute, The Rockefeller University, New York, NY, United StatesLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, FranceSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States2Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris Assistance Publique – Hopitaux de Paris (AP-HP), Paris, FranceLaboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, BrazilGraduate program in Molecular and Cellular Biology, Department of Genetics and Molecular Biology – Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil3Laboratory Research Unit, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil4National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, Rio Grande do Sul, Brazil5Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilInborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1472957/fullSCIDcase reportJAK3whole exome sequencingprolonged SARS-CoV-2inborn errors of immunity |
| spellingShingle | Renan Cesar Sbruzzi Renan Cesar Sbruzzi Mayara Jorgens Prado Bibiana Fam Bibiana Fam Helena Ashton Prolla Helena Ashton Prolla Alessandra Hellwig Grazielle Motta Rodrigues Fernanda de-Paris Mariana Jobim Osvaldo Artigalás Osvaldo Artigalás Yoann Seeleuthner Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jean-Laurent Casanova Jacinta Bustamante Jacinta Bustamante Jacinta Bustamante Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Fernanda Sales Luiz Vianna Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 Frontiers in Immunology SCID case report JAK3 whole exome sequencing prolonged SARS-CoV-2 inborn errors of immunity |
| title | Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 |
| title_full | Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 |
| title_fullStr | Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 |
| title_full_unstemmed | Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 |
| title_short | Case report: A novel JAK3 homozygous variant in a patient with severe combined immunodeficiency and persistent COVID-19 |
| title_sort | case report a novel jak3 homozygous variant in a patient with severe combined immunodeficiency and persistent covid 19 |
| topic | SCID case report JAK3 whole exome sequencing prolonged SARS-CoV-2 inborn errors of immunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1472957/full |
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