The article presents a systematic review of publications devoted to the study of genetic markers of severe pneumonia.The aim of the study was to compile a list of genetic markers that contribute to a severe course of pneumonia on the basis of the published data.In the current study, we searched for and analyzed articles published between January 2000 and April 2021. Following the search for and subsequent selection of articles, a list of 10 publications was compiled, which demonstrated a clear association of certain gene variants with severe and complicated pneumonia. Finally, we made a list of genetic markers of severe pneumonia consisting of 16 polymorphisms in 12 genes (CD86, IL6, IL10, PAI1, TNFα, HMGB1, ATG16L1, AGTR1, GCLC, CAT, IFNγ, FCGR2A).These genetic markers of severe and complicated pneumonia are responsible for various innate immune responses. The odds ratio for complicated pneumonia with a risk allele in the polymorphisms in the mentioned genes ranges from 1.39 to 4.28. To understand molecular and genetic mechanisms of severe pneumonia, further investigation of the effect of these genetic factors on the outcomes of pneumonia in different groups of patients with a simultaneous assessment of the cumulative effect of genetic variants and genetic interactions is required.
Substantial background level of replication stress is a feature of embryonic and induced pluripotent stem cells (iPSCs), which can predispose to numerical and structural chromosomal instability, including recurrent aberrations of Chromosome 12. In differentiated cells, replication stress-sensitive genomic regions, including common fragile sites, are widely mapped through mitotic chromosome break induction by mild Aphidicolin treatment, an inhibitor of replicative polymerases. IPSCs exhibit lower apoptotic threshold and higher repair capacity hindering fragile site mapping. Caffeine potentiates genotoxic effects and abrogates G2/M checkpoint delay induced by chemical and physical mutagens. Using 5-ethynyl-2'-deoxyuridine (EdU) for replication labeling, we characterized the mitotic entry dynamics of asynchronous iPSCs exposed to Aphidicolin and/or Caffeine. Under the adjusted timing of replication stress exposure accounting revealed cell cycle delay, higher metaphase chromosome breakage rate was observed in iPSCs compared to primary lymphocytes. Using differential chromosome staining and subsequent locus-specific fluorescent in situ hybridization, we mapped the FRA12L fragile site spanning the large neuronal ANKS1B gene at 12q23.1, which may contribute to recurrent Chromosome 12 missegregation and rearrangements in iPSCs. Publicly available data on the ANKS1B genetic alterations and their possible functional impact are reviewed. Our study provides the first evidence of common fragile site induction in iPSCs and reveals potential somatic instability of a clinically relevant gene during early human development and in vitro cell expansion.
Common variable immunodeficiency (CVID) is one form of the primary immunodeficiencies (PIDs). CVID is characterized by variable clinical manifestations. Genetic alteration is a cause of the disease in many cases. In the current paper we described Patient N of 45 years old, who have been suffering from frequent various infections and therefore attended an immunologist and clinical geneticist. Immunoglobulins (Ig) A, M, and G deficiency was found in the patient. As a result of medical genetic counselling primary immunodeficiency has been suggested as a diagnosis. Further molecular genetic testing using clinical exome sequencing (Next Generation Sequencing method) revealed a likely-pathogenic variant c.204dupA (p.Leu69ThrfsX12, rs72553875) of TNFRSF13B gene in the patient. The gene variant was found in homozygous state. According to the international medical literature and genomic databases TNFRSF13B gene mutations lead to the CVID development and in some patients are characterized by isolated IgA deficiency and in the other group of patients can lead to decrease of IgA, IgM, and IgG. The patient had a family history of cancer and autoimmune inflammatory bowel disease (erosive-ulcerative enterocolitis). Moreover, one sibling of the patient died at the age of 3 weeks from complications of toxoplasmosis infection. The other sibling of 51 years old have been also suffering from recurrent infectious diseases. Thus, the genetic cause of the disease was identified in the proband. It has been shown that homozygosity for variant c.204dupA of TNFRSF13B gene is characterized by the deficiency of all three classes of Ig. Medical genetic counselling and modern molecular genetic methods application is an important step in management of people with signs of immunodeficiency. Such approach helps to make a diagnosis to the patient, to find an exact molecular reason of the condition, to use effective treatment, and to perform preventive measures in patient`s family.
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