Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation

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.

Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation

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dc.contributor.author Hagl, Beate
dc.contributor.author Spielberger, Benedikt D.
dc.contributor.author Thoene, Silvia
dc.contributor.author Bonnal, Sophie
dc.contributor.author Mertes, Christian
dc.contributor.author Winter, Christof
dc.contributor.author Nijman, Isaac J.
dc.contributor.author Verduin, Shira
dc.contributor.author Eberherr, Andreas C.
dc.contributor.author Puel, Anne
dc.contributor.author Schindler, Detlev
dc.contributor.author Ruland, Jürgen
dc.contributor.author Meitinger, Thomas
dc.contributor.author Gagneur, Julien
dc.contributor.author Orange, Jordan S.
dc.contributor.author van Gijn, Marielle E.
dc.contributor.author Renner, Ellen D.
dc.date.accessioned 2019-12-09T09:23:00Z
dc.date.available 2019-12-09T09:23:00Z
dc.date.issued 2018
dc.description.abstract 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.
dc.description.sponsorship 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.).
dc.format.mimetype application/pdf
dc.identifier.citation Hagl B, Spielberger BD, Thoene S, Bonnal S, Mertes C, Winter C et al. Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation. Sci Rep. 2018;8(1):16719. DOI: 10.1038/s41598-018-34953-z
dc.identifier.doi http://dx.doi.org/10.1038/s41598-018-34953-z
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/43117
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Scientific Reports. 2018;8(1):16719
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/633974
dc.rights © 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/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Disease genetics
dc.subject.keyword Genetic testing
dc.subject.keyword Immunological deficiency syndromes
dc.subject.keyword Primary immunodeficiency disorders
dc.subject.keyword RNA splicing
dc.title Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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