Combined immunodeficiency associated with DOCK8 mutations.
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.
Zhang
Qian
Q
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Davis
Jeremiah C
JC
Lamborn
Ian T
IT
Freeman
Alexandra F
AF
Jing
Huie
H
Favreau
Amanda J
AJ
Matthews
Helen F
HF
Davis
Joie
J
Turner
Maria L
ML
Uzel
Gulbu
G
Holland
Steven M
SM
Su
Helen C
HC
D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008297:Male; D010375:Pedigree; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D012874:Skin Diseases, Infectious / Q000235:genetics / Q000276:immunology
C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007136:Immunoglobulins