Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation
Year: 2018
Type: article
Study design: Case Report
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.
Source: Scientific Reports
Institutions: Helmholtz Munich, Technical University of Munich, Ludwig-Maximilians-Universität München, German Cancer Research Center, TUM Klinikum, Deutsches Konsortium für Translationale Krebsforschung, Universitat Pompeu Fabra, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, University Medical Center Utrecht, Sorbonne Paris Cité, Human Genetic of Infectious Diseases, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Rockefeller University, University of Würzburg, German Center for Infection Research, Institut für Humangenetik, Baylor College of Medicine, Texas Children's Hospital, CK-CARE, Hochgebirgsklinik Davos
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W2899524698