Immune deficiencies, infection, and systemic immune disordersThe extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency
Section snippets
Patients and control subjects
We enrolled a cohort of 82 patients from 60 families in a worldwide collaboration. All patients fulfilled the following inclusion criteria for this study: signed informed consent forms, strong clinical suspicion of AR-HIES according to the referring immunologist, and available samples of genomic DNA or RNA. Of the 82 patients, 40 were male, and 42 were female. Forty-seven of the patients were also described by Aydin et al in a separate study (accepted for publication in the Journal of Clinical
Identification of DOCK8 deficiency
Of the 82 subjects studied in 60 families, we diagnosed DOCK8 deficiency in 64 patients from 50 families (see Fig E1). For 60 patients from 46 unrelated families, a homozygous or compound heterozygous mutation was identified in DOCK8 (Fig 1 and see Table E3 in this article's Online Repository at www.jacionline.org), for a total of 40 distinct mutations. For 4 patients from 4 families (ARH018, ARH019, ARH006, and ARH007), the DOCK8 mutation could not be identified by means of sequencing because
Discussion
Here we report 25 new mutations causing human DOCK8 deficiency and symptoms that were previously unrecognized to occur in patients with DOCK8 deficiency. Early diagnosis of DOCK8 deficiency is important to facilitate an adequate treatment, such as hematopoietic stem cell transplantation (HSCT).16, 17, 18, 19, 20
DOCK8 deficiency has a high mortality at a young age, with more frequent severe infections and malignancy, and therefore HSCT should be considered. In contrast, conflicting results have
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Supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). The research was funded in part by the European Community's 7th Framework Programmes FP7/2007-2013 under grant agreement Health-F5-2008-223292 (Euro Gene Scan), by a Marie Curie Excellence Grant (to B.G.; MEXT-CT-2006-042316-PIAID), and by National Institutes of Health grants 5R01AI065617 and 1R21AI087627 (to T.A.C.). This research was supported in part by a grant from the Scientific and Technological Research Council of Turkey (Tubitak, grant no. 1059B191300622). This research was supported in part by the Intramural Research program of the National Institutes of Health, NLM, and NIAID.
Disclosure of potential conflict of interest: K. R. Engelhardt has received research support from BMBF (BMBF 01EO1303) and the European Union (EU; MEXT-CT-2006-042316-PIAID). E. M. Gertz and Alejandro A. Schäffer are employed by the National Institutes of Health (NIH). R. Ceja is employed by Children's Hospital Boston. I. Schulze has received lecture fees from CSL Behring and Octapharma. T. Niehues has received lecture fees from CSL Behring, Infectopharma, and Novartis. M. Dasouki has received research support from Genzyme Corporation and Amicus Therapeutics. A. Jones has received lecture fees and support for attending meetings from CSL Behring. M.-R. Barbouche is employed by the Ministry of Health of Tunisia. R. S. Geha is employed by Boston Children's Hospital, has received research support from the NIH (5R01AI100315), and received grant support from the Dubai-Harvard Foundation for Medical Research. T. A. Chatila has received research support from the NIH (5R01AI065617 and 1R21AI087627). B. Grimbacher has received research support from BMBF (BMBF 01EO1303), the EU (MEXT-CT-2006-042316-PIAID), and Helmholtz (DZIF 8000805-3); is employed by UCL and UKL-FR; and has received lecture fees from CSL, Baxter, and Biotest. The rest of the authors declare that they have no relevant conflicts of interest.
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These authors contributed equally to this work.