McGhee, S. A.Engelhardt, K.Winkler, S.Sassi, A.Woellner, C.Lopez-Herrera, G.Chen, A.Kim, H.Garcia Lloret, M.Schulze,I.Ehl, S.Thiel, J.Pfeifer, D.Veelken, H.Niehues, T.Siepermann, K.Weinspach, S.Reisli, I.Keleş, S.Genel, F.Kütükçüker, N.Camcıoğlu, Y.Somer, A.Karakoç-Aydıner, E.Barlan, I.2020-03-262020-03-262010McGhee, S. A., Engelhardt, K., Winkler, S., Sassi, A., Woellner, C., Lopez-Herrera, G., Chen, A., Kim, H., Garcia Lloret, M., Schulze,I., Ehl, S., Thiel, J., Pfeifer, D., Veelken, H., Niehues, T., Siepermann, K., Weinspach, S., Reisli, I., Keleş, S., Genel, F., Kütükçüker, N., Camcıoğlu, Y., Somer, A., Karakoç-Aydıner, E., Barlan, I., (2010). DOCK8 Deletions and Mutations are Associated with the Autosomal Recessive Hyper-IgE Phenotype. Journal of Allergy and Clinical Immunology, 125(2), 356. doi: org/10.1016/j.jaci.2010.01.0060091-6749https://dx.doi.org/10.1016/j.jaci.2010.01.006https://hdl.handle.net/20.500.12395/2478966th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology -- FEB 26-MAR 02, 2010 -- New Orleans, LARATIONALE: Many patients who have a hyper-IgE like phenotype do not have mutations in STAT3 and show an autosomal recessive pattern of inheritance. The genetic cause of the immune deficiency is unexplained. METHODS: We analyzed 27 subjects with an autosomal recessive hyperIgE syndrome phenotype by mapping arrays and sequencing. Subjects were considered to have AR-HIES if they had no skeletal findings and primarily viral infections with a HIES score > 22. We performed copy number analysis and homozygosity mapping to implicate candidate loci. RESULTS: Five subjects had homozygous or compound heterozygous subtelomeric deletions involving 9p24.3, with the minimally deleted region involving only one gene, DOCK8. Sequencing of DOCK8 in the remaining patients showed nonsense and splice site mutations as well as single exon deletions within DOCK8 in 16 patients from 9 families. Patients with DOCK8 deficiency have pneumonia, skin abscesses, severe viral infections and candidiasis. Serum IgE was markedly elevated with profound eosinophilia. T cells from patients with DOCK8 deficiency had reduced proliferation from anti-CD3 stimulation. CONCLUSIONS: Deletions and mutations in DOCK8 are associated with the autosomal recessive hyper-IgE syndrome, as was also found by Zhang, et al (NEJM 2009;361:2046-55). Though its function is unknown, DOCK8 interacts with the cytoskeleton and may alter dendritic cell function, T-cell function, or both. Breakpoints for deletions appear to be near Alu Jb sequences, suggesting the possibility of retrotransposon activity as a mechanism for deletion. Genomic copy number variants are an important, newly appreciated mechanism underlying primary immune deficiency and can provide clues for disease gene identification.en10.1016/j.jaci.2010.01.006info:eu-repo/semantics/openAccessConference Object1252AB356AB356WOS:000280204100931Q1