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Hagl, B. ; Spielberger, B.D. ; Thoene, S.* ; Bonnal, S.* ; Mertes, C.* ; Winter, C.* ; Nijman, I.J.* ; Verduin, S.* ; Eberherr, A.C. ; Puel, A.* ; Schindler, D.* ; Ruland, J.* ; Meitinger, T. ; Gagneur, J.* ; Orange, J.S.* ; van Gijn, M.E.* ; Renner, E.D.

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

Sci. Rep. 8:16719 (2018)

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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 DOCKS 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 DOCKS variant c.4626 76A > 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 DOCKS 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Gtpase-activating Protein; Cytokinesis 8 Dock8; Cd8(+) T-cells; Primary Immunodeficiencies; Genetic-variation; Stat3 Mutations; Deficiency; Dedicator; Differentiation; Phenotype

ISSN (print) / ISBN 2045-2322

e-ISSN 2045-2322

Journal Scientific Reports

Quellenangaben Volume: 8, Issue: 1, Article Number: 16719

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Environmental Medicine (IEM)
Institute of Human Genetics (IHG)