Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation
In hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCK8 and STAT3 and correspondin...
| Autores: | , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/43117 |
| Acceso en línea: | http://hdl.handle.net/10230/43117 http://dx.doi.org/10.1038/s41598-018-34953-z |
| Access Level: | acceso abierto |
| Palabra clave: | Disease genetics Genetic testing Immunological deficiency syndromes Primary immunodeficiency disorders RNA splicing |
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Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutationHagl, BeateSpielberger, Benedikt D.Thoene, SilviaBonnal, SophieMertes, ChristianWinter, ChristofNijman, Isaac J.Verduin, ShiraEberherr, Andreas C.Puel, AnneSchindler, DetlevRuland, JürgenMeitinger, ThomasGagneur, JulienOrange, Jordan S.van Gijn, Marielle E.Renner, Ellen D.Disease geneticsGenetic testingImmunological deficiency syndromesPrimary immunodeficiency disordersRNA splicingIn hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCK8 and STAT3 and corresponding molecular testing has improved diagnosis. Yet, in a child and her newborn sibling with HIES phenotype molecular diagnosis was misleading. Extensive analyses driven by the clinical phenotype identified an intronic homozygous DOCK8 variant c.4626 + 76 A > G creating a novel splice site as disease-causing. While the affected newborn carrying the homozygous variant had no expression of DOCK8 protein, in the index patient molecular diagnosis was compromised due to expression of altered and wildtype DOCK8 transcripts and DOCK8 protein as well as defective STAT3 signaling. Sanger sequencing of lymphocyte subsets revealed that somatic alterations and reversions revoked the predominance of the novel over the canonical splice site in the index patient explaining DOCK8 protein expression, whereas defective STAT3 responses in the index patient were explained by a T cell phenotype skewed towards central and effector memory T cells. Hence, somatic alterations and skewed immune cell phenotypes due to selective pressure may compromise molecular diagnosis and need to be considered with unexpected clinical and molecular findings.This work was supported by the Wilhelm-Sander foundation (2013.015.2), the German Research Foundation (DFG RE2799/6-1), the Fritz-Bender foundation (all to E.D.R.), the EU Horizon2020 Collaborative Research Project SOUND (633974) (to J.G.), and the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa, and to the EMBL partnership and of the CERCA Programme/Generalitat de Catalunya. Data included in this publication are part of a medical thesis at the School of Medicine, LMU Munich (B.D.S.).Nature Research201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/43117http://dx.doi.org/10.1038/s41598-018-34953-zreponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésScientific Reports. 2018;8(1):16719info:eu-repo/grantAgreement/EC/H2020/633974© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/431172026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| title |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| spellingShingle |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation Hagl, Beate Disease genetics Genetic testing Immunological deficiency syndromes Primary immunodeficiency disorders RNA splicing |
| title_short |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| title_full |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| title_fullStr |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| title_full_unstemmed |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| title_sort |
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation |
| dc.creator.none.fl_str_mv |
Hagl, Beate Spielberger, Benedikt D. Thoene, Silvia Bonnal, Sophie Mertes, Christian Winter, Christof Nijman, Isaac J. Verduin, Shira Eberherr, Andreas C. Puel, Anne Schindler, Detlev Ruland, Jürgen Meitinger, Thomas Gagneur, Julien Orange, Jordan S. van Gijn, Marielle E. Renner, Ellen D. |
| author |
Hagl, Beate |
| author_facet |
Hagl, Beate Spielberger, Benedikt D. Thoene, Silvia Bonnal, Sophie Mertes, Christian Winter, Christof Nijman, Isaac J. Verduin, Shira Eberherr, Andreas C. Puel, Anne Schindler, Detlev Ruland, Jürgen Meitinger, Thomas Gagneur, Julien Orange, Jordan S. van Gijn, Marielle E. Renner, Ellen D. |
| author_role |
author |
| author2 |
Spielberger, Benedikt D. Thoene, Silvia Bonnal, Sophie Mertes, Christian Winter, Christof Nijman, Isaac J. Verduin, Shira Eberherr, Andreas C. Puel, Anne Schindler, Detlev Ruland, Jürgen Meitinger, Thomas Gagneur, Julien Orange, Jordan S. van Gijn, Marielle E. Renner, Ellen D. |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Disease genetics Genetic testing Immunological deficiency syndromes Primary immunodeficiency disorders RNA splicing |
| topic |
Disease genetics Genetic testing Immunological deficiency syndromes Primary immunodeficiency disorders RNA splicing |
| description |
In hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCK8 and STAT3 and corresponding molecular testing has improved diagnosis. Yet, in a child and her newborn sibling with HIES phenotype molecular diagnosis was misleading. Extensive analyses driven by the clinical phenotype identified an intronic homozygous DOCK8 variant c.4626 + 76 A > G creating a novel splice site as disease-causing. While the affected newborn carrying the homozygous variant had no expression of DOCK8 protein, in the index patient molecular diagnosis was compromised due to expression of altered and wildtype DOCK8 transcripts and DOCK8 protein as well as defective STAT3 signaling. Sanger sequencing of lymphocyte subsets revealed that somatic alterations and reversions revoked the predominance of the novel over the canonical splice site in the index patient explaining DOCK8 protein expression, whereas defective STAT3 responses in the index patient were explained by a T cell phenotype skewed towards central and effector memory T cells. Hence, somatic alterations and skewed immune cell phenotypes due to selective pressure may compromise molecular diagnosis and need to be considered with unexpected clinical and molecular findings. |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2019 2019 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/43117 http://dx.doi.org/10.1038/s41598-018-34953-z |
| url |
http://hdl.handle.net/10230/43117 http://dx.doi.org/10.1038/s41598-018-34953-z |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
| dc.relation.none.fl_str_mv |
Scientific Reports. 2018;8(1):16719 info:eu-repo/grantAgreement/EC/H2020/633974 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Nature Research |
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Nature Research |
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