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Novel deletion mutation in Bruton's tyrosine kinase results in X-linked agammaglobulinemia: A case report.

ABSTRACT: BACKGROUND:X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton's tyrosine kinase (BTK). We found a new mutation point and summarized the correlation analysis and performed a literature review. CASE SUMMARY:The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunodeficiency or recurrent infection history among his family members. Agammaglobulinemia was characterized as follows: Immunoglobulin (Ig) A, 90.0 mg/dL (90-450 mg/dL); IgG, 20.0 mg/dL (800-1800 mg/dL); and IgM, 18.0 mg/dL (60-280 mg/dL). Notably, the assessment of IgG subtypes revealed the following very low levels: Subtype 1, 0.26 g/L (3.62-12.28 g/L); subtype 2, 0.10 g/L (0.57-2.9 g/L); subtype 3, 0.009 g/L (0.129-0.789 g/L); and subtype 4, 0.003 g/L (0.013-1.446 g/L). Cellular immunological test results were as follows: CD3, 74.6% (50%-84.0%); CD4, 47.3% (27.0%-51.0%); and CD8, 24.9% (15.0%-44.0%). A de novo hemizygous deletion in BTK was detected: c.902_c.904delAAG/p.E301del. Transcript levels of the mutant BTK were similar to those of the wild-type gene, though overexpression resulted in markedly reduced levels of mutant BTK (9.49% ± 1.58%), relative to the wild-type BTK (75.8% ± 2.98%, P < 0.01). CONCLUSION:This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK (c.902_c.904delAAG/p.E301del). The mutation resulted in markedly reduced BTK protein stability in vitro.

SUBMITTER: Hu XM

PROVIDER: S-EPMC7479573 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Novel deletion mutation in Bruton's tyrosine kinase results in X-linked agammaglobulinemia: A case report.

Hu Xiao-Mei XM Yuan Ke K Chen Hong H Chen Chun C Fang Yan-Lan YL Zhu Jian-Fang JF Liang Li L Wang Chun-Lin CL

World journal of clinical cases 20200901 17

<h4>Background</h4>X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton's tyrosine kinase (<i>BTK</i>). We found a new mutation point and summarized the correlation analysis and performed a literature review.<h4>Case summary</h4>The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunode ...[more]

PMID: 32953865

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Project description:X-linked agammaglobulinemia (XLA) is a monogenic primary immune deficiency characterized by very low levels of immunoglobulins and greatly increased risks for recurrent and severe infections. Patients with XLA have a loss-of-function mutation in the Bruton's tyrosine kinase (BTK) gene and fail to produce mature B lymphocytes. Gene editing in the hematopoietic stem cells of XLA patients to correct or replace the defective gene should restore B cell development and the humoral immune response. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 platform to precisely target integration of a corrective, codon-optimized BTK complementary DNA (cDNA) cassette into its endogenous locus. This process is driven by homologous recombination and should place the transgenic BTK under transcriptional control of its endogenous regulatory elements. Each integrated copy of this cDNA in BTK-deficient K562 cells produced only 11% as much BTK protein as the wild-type gene. The donor cDNA was modified to include the terminal intron of the BTK gene. Successful integration of the intron-containing BTK donor led to a nearly twofold increase in BTK expression per cell over the base donor. However, this donor variant was too large to package into an adeno-associated viral vector for delivery into primary cells. Donors containing truncated variants of the terminal intron also produced elevated expression, although to a lesser degree than the full intron. Addition of the Woodchuck hepatitis virus posttranscriptional regulatory element led to a large boost in BTK transgene expression. Combining these modifications led to a BTK donor template that generated nearly physiological levels of BTK expression in cell lines. These reagents were then optimized to maximize integration rates into human hematopoietic stem and progenitor cells, which have reached potentially therapeutic levels in vitro. The novel donor modifications support effective gene therapy for XLA and will likely assist in the development of other gene editing-based therapies for genetic disorders.

Project description:BackgroundX-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder.MethodsWe detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR .ResultsWe evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy.ConclusionWe confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.

Project description:X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton's tyrosine kinase (BTK) gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. HLH is a life-threatening condition with manifestations of non-remitting fever, hepatosplenomegaly, cytopenias, coagulopathy, lipid disorder, and multiple organ failure. It is caused by the immune dysregulation between cytotoxic T cells, NK cells, and histiocytes. The treatment is based on HLH-2004 protocol including immunotherapy, chemotherapy, supportive therapy, and stem cell transplantation. However, as we know more about the classification and pathophysiology of HLH, the treatment is modified. T-cell-directed immunotherapy is effective in patients with primary HLH, and strong immunosuppression is contraindicated in patients with severe ongoing infections or some primary immunodeficiency diseases (PIDs). Here, we report the case of a 7-year-old boy who presented with ecthyma gangrenosum and several episodes of pyogenic infections during childhood. At the age of 5 years, he exhibited cyclic HLH every 2-3 months. The remission of HLH episodes finally achieved after he received monthly Ig replacement therapy (400 mg/kg) at the 4th HLH. However, transient elevation of IgM was incidentally discovered after 6 cycles of monthly Ig replacement therapy. IgM-secreting multiple myeloma, Waldenström's macroglobulinemia, and lymphoma were excluded. The IgM levels then declined and returned to the normal range within a year. The patient and his parents received whole-genome sequencing analysis. It revealed a novel hemizygous c.1632-1G>A mutation in the BTK gene and XLA was diagnosed. XLA exhibits a spectrum of clinical and immunological presentations in patients. The identification of the mutation in the BTK gene contribute to an accurate diagnosis. Ig replacement therapy is the primary treatment for HLH in patients with XLA.

Dataset Information

Novel deletion mutation in Bruton's tyrosine kinase results in X-linked agammaglobulinemia: A case report.

Publications

Novel deletion mutation in Bruton's tyrosine kinase results in X-linked agammaglobulinemia: A case report.

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