DOCK8-related immunodeficiency syndrome (DIDS): novel deleterious mutations

Background and Aim : DOCK8 immunodeficiency syndrome (DIDS), which is the predominant form of autosomal recessive hyper IgE syndrome (AR-HIES) is a complex immunodeficiency disease characterized by elevated serum IgE levels, eosinophilia, depressed IgM levels, decreased IgA in the serum, severe atopy, sinopulmonary infections, recurrent viral and other infections, mucocutaneous candidiasis, and early-onset malignancy.Methods : The first patient was a 6-year old female with consanguineous parents and severe DIDS symptoms including mouth sores and inflammation, lip and tongue swelling, severe atopy, and fever. The second person, who had the same age as the first patient, had been suffered from asthma, atopic dermatitis, and had eosinophilia and elevated serum IgE levels. Since both patients’ parents were consanguineous, we assessed patients with whole exome sequencing (WES) and their relatives with sanger method. Results : The current research represents two novel homozygous mutations, deletion in the dedicator of cytokinesis 8 gene (DOCK8) exon 4-24 and frameshift deletion in exon24 of mentioned gene (c.2933-2934, p.Q978fs), in two different patients with HIES. Our bioinformatic analysis showed that these variations are pathogenic and result in truncated protein. The absence of this protein leads to eosinophilia, very high levels of serum IgE and impairs the ability of NK cells and T cells to maintain their morphologies when migrating within skin, causing skin cells deaths and poor control of virus infections in this tissue. Furthermore, the lack of DOCK8 prevents development, function, and survival of other lymphocyte subsets and impairs dendritic cell functions. Co-segregation analysis revealed the parents were heterozygous for the variants. Conclusion : These findings state vital role of DOCK8 in lymphocytes and for understanding the disease suggest further studies with special focus on DOCK8 role in regulating the processes.

Keywords:

DOCK8 , DIDS , immunodeficiency syndrome , WES