Abstract
DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.
Highlights
The dedicator of cytokinesis 8 (DOCK8) protein exerts critical roles in both humoral and cellular immune responses
Large deletions have been frequently reported in DOCK8-deficient patients [11], requiring including copy number variants (CNV) analysis in patients with complex phenotypes [12]
If whole exome/whole genome sequencing with CNV analysis cannot be performed, a combination of next generation sequencing (NGS), Single nucleotide polymorphism (SNP) array, or multiplex ligation-dependent probe amplification (MLPA) should be used
Summary
The dedicator of cytokinesis 8 (DOCK8) protein exerts critical roles in both humoral and cellular immune responses. Single nucleotide polymorphism (SNP) array and MLPA revealed the maternally inherited deletion of exons 1 to 3 (Figure 1C) Both variants are supposed for their nature to lead to a null DOCK8 phenotype being pathogenetic (class 5). Flow cytometric and western blot analysis showed markedly reduced, but not absent, DOCK8 expression in patient’s interleukin-2 (IL2)-PHA expanded Tcells, CD3+CD4+ and CD3+CD8+ while DOCK8 expression was absent in monocytes These results collectively suggested hypomorphic residual function in T-cells (Figures 3A, B). Sanger sequencing analysis performed on epithelial cells as well as on peripheral T-cells confirmed the presence of the heterozygous status for the T824A variant in all the lineages, excluding the possibility of somatic reversion for this variant, while a somatic reversion of the deletion was detected by MLPA analysis in patient’s T-cells blasts (Figures 1B, C). Chimerism will be checked every 14 days until day +180 and afterward once a month until 1 year after HSCT
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