Combined immunodeficiency associated with DOCK8 mutations

Qian Zhang, Jeremiah C. Davis, Ian T. Lamborn, Alexandra F. Freeman, Huie Jing, Amanda J. Favreau, Helen F. Matthews, Joie Davis, Maria L. Turner, Gulbu Uzel, Steven M. Holland, Helen C. Su

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS: We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS: Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS: Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

Original languageEnglish
Pages (from-to)2046-2055
Number of pages10
JournalNew England Journal of Medicine
Volume361
Issue number21
DOIs
Publication statusPublished - 19 Nov 2009
Externally publishedYes

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Cytokinesis
Virus Diseases
Skin
Immunoglobulin E
Mutation
Infection
Serum
Molluscum Contagiosum
Otitis Externa
T-Lymphocytes
T-Cell Leukemia
Protein Deficiency
Proteins
Comparative Genomic Hybridization
Papillomavirus Infections
T-Cell Lymphoma
Sequence Deletion
Sinusitis
Herpes Zoster
Lymphocyte Count

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, Q., Davis, J. C., Lamborn, I. T., Freeman, A. F., Jing, H., Favreau, A. J., ... Su, H. C. (2009). Combined immunodeficiency associated with DOCK8 mutations. New England Journal of Medicine, 361(21), 2046-2055. https://doi.org/10.1056/NEJMoa0905506

Combined immunodeficiency associated with DOCK8 mutations. / Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen F.; Davis, Joie; Turner, Maria L.; Uzel, Gulbu; Holland, Steven M.; Su, Helen C.

In: New England Journal of Medicine, Vol. 361, No. 21, 19.11.2009, p. 2046-2055.

Research output: Contribution to journalArticle

Zhang, Q, Davis, JC, Lamborn, IT, Freeman, AF, Jing, H, Favreau, AJ, Matthews, HF, Davis, J, Turner, ML, Uzel, G, Holland, SM & Su, HC 2009, 'Combined immunodeficiency associated with DOCK8 mutations', New England Journal of Medicine, vol. 361, no. 21, pp. 2046-2055. https://doi.org/10.1056/NEJMoa0905506
Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ et al. Combined immunodeficiency associated with DOCK8 mutations. New England Journal of Medicine. 2009 Nov 19;361(21):2046-2055. https://doi.org/10.1056/NEJMoa0905506
Zhang, Qian ; Davis, Jeremiah C. ; Lamborn, Ian T. ; Freeman, Alexandra F. ; Jing, Huie ; Favreau, Amanda J. ; Matthews, Helen F. ; Davis, Joie ; Turner, Maria L. ; Uzel, Gulbu ; Holland, Steven M. ; Su, Helen C. / Combined immunodeficiency associated with DOCK8 mutations. In: New England Journal of Medicine. 2009 ; Vol. 361, No. 21. pp. 2046-2055.
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AU - Matthews, Helen F.

AU - Davis, Joie

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N2 - BACKGROUND: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS: We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS: Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS: Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

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