ArticleScientific reports2018
Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Signal Transducer and Activator of Transcription 3 (STAT3) Variant p.K709N Causes Hyper-IgE Syndrome Likely by Impaired STAT3-Dimer Formation.European journal of immunology · 2025Article
- Somatic mutations in autoinflammatory and autoimmune disease.Nature reviews. Rheumatology · 2024Review
- DOCK8 deficiency due to a deep intronic variant in two kindreds with hyper-IgE syndrome.Clinical immunology (Orlando, Fla.) · 2024Article
- A deep intronic splice-alteringScience translational medicine · 2024Article
- Mapping the splicing landscape of the human immune system.Frontiers in immunology · 2023Article
- DOCK8-related Immunodeficiency Syndrome (DIDS): Report of Novel Mutations in Iranian Patients.Journal of molecular neuroscience : MN · 2021Article
- Reversion Mosaicism in Primary Immunodeficiency Diseases.Frontiers in immunology · 2021Review
- A deep intronic splice mutation ofProceedings of the National Academy of Sciences of the United States of America · 2019Article
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Authors and funding
17 authors at 8 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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