Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

Pillay, Bethany; Fusaro, Mathieu; Gray, Paul; Statham, Aaron L.; Burnett, Leslie; Bezrodnik, Liliana; Kane, Alisa; Tong, Winnie; Abdo, Chrystelle; Winter, Sarah; Chevalier, Samuel; Lévy, Romain; Masson, Cécile; Schmitt, Yohann; Bole, Christine; Malphettes, Marion; Macintyre, Elizabeth; Villartay, Jean‐Pierre de; Ziegler, John B.; Smart, Joanne; Peake, Jane; Aghamohammadi, Asghar; Hammarström, Lennart; Abolhassani, Hassan; Pïcard, Capucine; Fischer, Alain; Latour, Sylvain; Neven, Bénédicte; Tangye, Stuart G.; Cindy, S.

doi:10.1172/jci142434

Cited by 22 publications

(20 citation statements)

References 55 publications

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“…DOCK8 deficiency has been shown to disrupt B-cell responses to signals via TLR, BCR, CD40, and cytokines, especially IL-21 [29]. In one patient, Al-Herz et al found increased donor chimerism in the switched memory B-cell compartment, in agreement with recent findings of DOCK8 enrichment in the memory B-cells [32]. However, we did not analyze this in our patients but reduced switched memory B-cell numbers were not clearly associated with mixed chimerism in our cohort.…”

Section: Discussionsupporting

confidence: 69%

“…Conversely, we observed no relevant selective advantage for wild-type B-cells in vivo as evidenced by an overall lower but stable B-cell chimerism over time after HSCT, but subtle effects cannot be excluded due to the low number of patients. Myeloid chimerism was not available for our patients, but a selective advantage for wild-type DOCK8 in lymphoid cells, rather than myeloid cells, was previously shown [32].…”

Section: Discussionmentioning

confidence: 92%

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Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

et al. 2021

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Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 92%

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

et al. 2021

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“…These patients showed progressive clinical improvement after a history of severe clinical course early in life, although not all patients with reversion mutations have significant recovery. Reversion mutations have also been identified in other IEI, including in patients with leukocyte adhesion deficiency type-1 (LAD-1) [68], Xlinked lymphoproliferative disease (XLP) [69,70], and DOCK8 deficiency [71,72].…”

Section: Somatic Reversion Mutations In Ieimentioning

confidence: 99%

Genetic Mosaicism as a Cause of Inborn Errors of Immunity

Aluri

Cooper

2021

J Clin Immunol

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Inborn errors of immunity (IEIs) are a heterogeneous group of disorders due to genetic defects in the immune response that have a broad clinical spectrum. Diagnosis of the precise genetic cause of IEI has led to improved care and treatment of patients; however, genetic diagnosis using standard approaches is only successful in ~40% of patients and is particularly challenging in “sporadic” cases without a family history. Standard genetic testing for IEI evaluates for germline changes in genes encoding proteins important for the immune response. It is now clear that IEI can also arise from de novo mutations leading to genetic variants present in germ cells and/or somatic cells. In particular, somatic mosaicism, i.e., post-zygotic genetic changes in DNA sequence, is emerging as a significant contributor to IEI. Testing for somatic mosaicism can be challenging, and both older sequencing techniques such as Sanger sequencing and newer next-generation sequencing may not be sensitive enough to detect variants depending on the platform and analysis tools used. Investigation of multiple tissue samples and specifically targeting sequence technologies to detect low frequency variants is important for detection of variants. This review examines the role and functional consequences of genetic mosaicism in IEI. We emphasize the need to refine the current exome and genome analysis pipeline to efficiently identify mosaic variants and recommend considering somatic mosaicism in disease discovery and in the first-tier of genetic analysis.

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“…Subsequently, IPEX-like phenotype and active colitis have been associated with DOCK8 deficiency (13,23). Autoimmune phenomena, in our case SC, have been related to defective number and function of T reg , depending on DOCK8 deficiency (15,23).…”

Section: Discussionmentioning

confidence: 73%

“…lack of markedly elevated IgE levels, hypereosinophilia, and/or severe viral skin infections), patients still experienced disease progression and severe or fatal complications (7,8). Interestingly, while preparing this manuscript, clinical improvement over time has been described in 3 DOCK8-deficient patients (15). Authors demonstrated that somatic reversion of one of the mutated alleles restored lymphocyte survival, differentiation and function.…”

Section: Discussionmentioning

confidence: 95%

Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

et al. 2021

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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.

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Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

Cited by 22 publications

References 55 publications

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

Genetic Mosaicism as a Cause of Inborn Errors of Immunity

Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

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