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A Novel Mutation in the NCF2 Gene in a CGD Patient With Chronic Recurrent Pneumopathy.

ABSTRACT: Chronic granulomatous disease (CGD) is an inherited, genetically heterogeneous disease characterized by defective phagocytic cell microbicidal function, leading to increased susceptibility to bacterial and fungal infections. CGD is caused by mutations in components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, which is responsible for reactive oxygen species production during phagocytosis. Mutations in the neutrophil cytosolic factor 2 (NCF2) gene account for <5% of all cases. Here, we report a case of a 2-year-old female with persistent recurrent pneumopathy, even under trimethoprim-sulfamethoxazole (TMP-SMX) and itraconazole prophylaxis combined with IFN? treatment. Genetic analysis revealed a novel homozygous mutation in NCF2, sequence depletion in a splicing region (c.256_257+2delAAGT NM_000433), leading to a K86Ifs*2 residue change in the p67-phox protein.

SUBMITTER: de Albuquerque JAT

PROVIDER: S-EPMC6776604 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Novel Mutation in the <i>NCF2</i> Gene in a CGD Patient With Chronic Recurrent Pneumopathy.

de Albuquerque Jose Antonio Tavares JAT Lima Alessandra Miramontes AM de Oliveira Junior Edgar Borges EB Ishizuka Edson Kiyotaka EK Aragão-Filho Walmir Cutrim WC Bengala Zurro Nuria N Mayumi Chiba Sônia S Fernandes Fátima Rodrigues FR Condino-Neto Antonio A

Frontiers in pediatrics 20190927

Chronic granulomatous disease (CGD) is an inherited, genetically heterogeneous disease characterized by defective phagocytic cell microbicidal function, leading to increased susceptibility to bacterial and fungal infections. CGD is caused by mutations in components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, which is responsible for reactive oxygen species production during phagocytosis. Mutations in the neutrophil cytosolic factor 2 (<i>NCF2</i>) gene account for ...[more]

PMID: 31612120

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Project description:BackgroundChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.Case presentationA 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient's neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.ConclusionsThe case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient's ethnic group. Other mutations in NCF2 have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.

Project description:IntroductionInborn errors of immunity (IEI) are a heterogeneous group of disorders characterized by increased risk of infections, autoimmunity, autoinflammatory diseases, malignancy and allergy. Next-generation sequencing has revolutionized the identification of genetic background of these patients and assists in diagnosis and treatment. In this study, we identified a probable unique monogenic cause of IEI, and evaluated the immunological methods and pathogenic detections.MethodsA family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.ResultsThe patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn't detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.ConclusionWe identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.

Dataset Information

A Novel Mutation in the NCF2 Gene in a CGD Patient With Chronic Recurrent Pneumopathy.

Publications

A Novel Mutation in the <i>NCF2</i> Gene in a CGD Patient With Chronic Recurrent Pneumopathy.

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