Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID
Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.644687/full |
| _version_ | 1818655668999028736 |
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| author | Jolanda Steininger Alexander Leiss-Piller Christoph B. Geier Raphael Rossmanith Reem Elfeky David Bra Herbert Pichler Anita Lawitschka Natascha Zubarovskaya Gottfried Artacker Susanne Matthes-Leodolter Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf |
| author_facet | Jolanda Steininger Alexander Leiss-Piller Christoph B. Geier Raphael Rossmanith Reem Elfeky David Bra Herbert Pichler Anita Lawitschka Natascha Zubarovskaya Gottfried Artacker Susanne Matthes-Leodolter Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf |
| author_sort | Jolanda Steininger |
| collection | DOAJ |
| description | Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3’ splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαβ/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT. |
| first_indexed | 2024-12-17T03:13:21Z |
| format | Article |
| id | doaj.art-2b77362089564493a8a81cc8686be4d6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T03:13:21Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2b77362089564493a8a81cc8686be4d62022-12-21T22:05:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-04-011210.3389/fimmu.2021.644687644687Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCIDJolanda Steininger0Alexander Leiss-Piller1Christoph B. Geier2Raphael Rossmanith3Reem Elfeky4David Bra5Herbert Pichler6Anita Lawitschka7Natascha Zubarovskaya8Gottfried Artacker9Susanne Matthes-Leodolter10Martha M. Eibl11Martha M. Eibl12Hermann M. Wolf13Hermann M. Wolf14Immunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaDepartment of Clinical Immunology, Royal Free Hospital, London, United KingdomImmunology Outpatient Clinic, Vienna, AustriaDepartment of Pediatrics, St. Anna Kinderspital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna, AustriaDepartment of Pediatrics, St. Anna Kinderspital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna, AustriaDepartment of Pediatrics, St. Anna Kinderspital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna, AustriaDepartment of Paediatrics and Adolescent Medicine, Danube Hospital, Vienna, AustriaDepartment of Pediatrics, St. Anna Kinderspital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaBiomedizinische Forschungs GmbH, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaSigmund Freud Private University- Medical School, Vienna, AustriaMutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3’ splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαβ/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT.https://www.frontiersin.org/articles/10.3389/fimmu.2021.644687/fullsevere combined immunodeficiencyX-SCIDIL2RGsomatic mosaicismearly engraftmentsecond-site mutation |
| spellingShingle | Jolanda Steininger Alexander Leiss-Piller Christoph B. Geier Raphael Rossmanith Reem Elfeky David Bra Herbert Pichler Anita Lawitschka Natascha Zubarovskaya Gottfried Artacker Susanne Matthes-Leodolter Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID Frontiers in Immunology severe combined immunodeficiency X-SCID IL2RG somatic mosaicism early engraftment second-site mutation |
| title | Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID |
| title_full | Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID |
| title_fullStr | Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID |
| title_full_unstemmed | Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID |
| title_short | Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID |
| title_sort | case report a novel il2rg frame restoring rescue mutation mimics early t cell engraftment following haploidentical hematopoietic stem cell transplantation in a patient with x scid |
| topic | severe combined immunodeficiency X-SCID IL2RG somatic mosaicism early engraftment second-site mutation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.644687/full |
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