First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature

Abstract

Background Dedicator of cytokinesis 2 (DOCK2) deficiency is an inborn error of immunity characterized by cellular and humoral immunological abnormalities leading to early-onset infections. Case presentation We reported a novel case of a 27 months old girl presenting with recurrent pneumonia and a history of skeletal tuberculosis at the age of 19-month-old. Her immunological workup revealed persistent lymphopenia and low CD4 + T cell count along with elevated levels of CD19 +, CD20 +, CD16 +, and CD56 + cells. Furthermore, she had a high level of immunoglobulin (Ig) E and a slightly reduced IgM level with a non-protective antibody titer against diphtheria. The whole-exome sequencing (WES) analysis identified a homozygous frameshift deletion mutation (c.1512delG, p.I505Sfs*28) in exon 16 of the DOCK2 gene. We also conducted electronic searches in PubMed, Web of Science, and Scopus databases and reviewed the articles reporting patients with DOCK2 deficiency. The literature search yielded 14 DOCK2-deficient patients suffering from both cellular and humoral immune defects leading to early-onset infections, particularly human herpesvirus (HHV) infection. Conclusion DOCK2 deficiency should be considered in the context of severe or unusual early-onset infections, especially HHV infections, in a patient with a probable clinical diagnosis of combined immunodeficiency. We also recommended that DOCK2-deficient patients might benefit from T-cell receptor excision circle (TREC) assay as part of the routine newborn screening program.

A novel DOCK2 variant in siblings with severe combined immunodeficiency

“…Patients with SCID are highly susceptible to early-onset severe infections and have a lethal outcome if not treated with haematopoietic stem cell transplantation (HSCT) or gene therapy early in life. [4][5][6] Whole-genome sequencing (WGS) is useful for identification of gene defects and has proven valuable in the diagnostics of DOCK2-deficient patients presenting with symptoms compatible with SCID. 5,6 Herein, we report two siblings diagnosed with SCID caused by a novel pathogen splice site variant in the DOCK2 in homozygous state, not previously reported in the literature.…”

“…[4][5][6] Whole-genome sequencing (WGS) is useful for identification of gene defects and has proven valuable in the diagnostics of DOCK2-deficient patients presenting with symptoms compatible with SCID. 5,6 Herein, we report two siblings diagnosed with SCID caused by a novel pathogen splice site variant in the DOCK2 in homozygous state, not previously reported in the literature. The siblings were born to first-degree consanguineous Turkish parents.…”

“…Since then, a total of 20 patients with SCID and variants in DOCK2, including the two patients presented herein, have been reported in the literature. 2,3,5,6,8,9 Three of these patients were not described in detail; hence, no details exist regarding time of symptom onset, relevant treatment or current status. 6 The remaining 17 patients presented with symptoms between ages 0 and 4 years with predominance of symptoms occurring in children less than 1 year.…”

Insights from DOCK2 in cell function and pathophysiology

“…Clinical and genetic characteristics of a DOCK2-deficient patient were reported in 2017 ( Alizadeh et al, 2018 ). DOCK2 deficiency is a congenital immunodeficiency and a rare autosomal recessive combined immunodeficiency presenting with very early onset, severe bacterial and viral infections ( Sharifinejad et al, 2021 ). The patient had T cell lymphopenia and reduced numbers of B cells and NK cells.…”

“…The presence of functionally normal T cells in a rare patient with CID has been reported and the girl was considered to suffer from CID. DOCK2-deficient patients were reported in 2019 and three patients with DOCK2 deficiency were reported in 2021 ( Alosaimi et al, 2019 ; Sharifinejad et al, 2021 ; Aytekin et al, 2021 ; D'Astous-Gauthier et al, 2021 ). DCOK2 deficiency patients presented with severe compound immune deficiency and the CD4 + T cell lymphopenia manifest in all DOCK2-deficient patients studied to date.…”