scholarly journals Genetic variants identified in children with recurrent infections

2021 ◽  
Vol 20 (4) ◽  
pp. 13-17
Author(s):  
A. S. Levina ◽  
E. N. Suspitsin ◽  
N. V. Skripchenko ◽  
O. V. Goleva ◽  
O. M. Ibragimova
Keyword(s):  
Immune System ◽  
Primary Immunodeficiency ◽  
Genetic Variants ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Recurrent Infections ◽  
Laboratory Studies ◽  
Inflammatory Disorders ◽  
Pathogenic Variants ◽  
Rare Genetic Variants

Currently, the most effective way to diagnose hereditary defects of the immune system is molecular genetic research, the results of which are evaluated in conjunction with the data of clinical and laboratory studies.Aims of the sudy: to evaluate the frequency and spectrum of rare genetic variants associated with the development of primary immunodeficiency (PID) in children with recurrent infections.Materials and methods: DNA samples from 113 children with recurrent infections were analyzed by targeted multigene sequencing of 338 PID-associated genes. Results: Pathogenic variants appropriate to the potential diagnosis of PID were identified in 8% of patients. Interestingly, 47.8% of children had variants associated with auto-inflammatory disorders.

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

P1392Next generation sequencing in lone atrial fibrillation patients

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
I Rudaka ◽  
D Rots ◽  
O Kalejs ◽  
L Gailite
Keyword(s):  
Atrial Fibrillation ◽  
Sudden Cardiac Death ◽  
Genetic Variants ◽  
Cardiac Death ◽  
Structural Heart Disease ◽  
Missense Variant ◽  
Lone Atrial Fibrillation ◽  
Excessive Alcohol Consumption ◽  
Pathogenic Variants ◽  
Rare Genetic Variants

Abstract Background. Minor part of atrial fibrillation (AF) patients develops the disease without any well-known risk factors, which is a particular form of the disease, known as a lone AF. Rare genetic variants were described as causative for lone AF. The aim of this study was to investigate occurrence of rare genetic variants in lone AF patients. Material and Methods. We performed Mendeliome sequencing for 21 lone AF patients. Lone AF was defined as AF in individuals younger than 65 years in the absence of cardiovascular or structural heart disease, endocrinologic or pulmonary disease, chronic kidney disease, obesity and excessive alcohol consumption. Data analysis was performed by current laboratory pipeline. We analyzed 453 cardiomyopathy, arrhythmias and sudden cardiac death related genes. Results. In eight out of 21 (38%) lone AF patients rare likely pathogenic variants were found (Table 1.). Seven rare truncating TTN variants and one LMNA missense variant were observed. Four unrelated patients were positive for the same TTN variant c.13696 C > T; p.(Gln4566Ter). The same variant was previously found in ARVC patient in our laboratory. Segregation analysis and phenotyping of relatives is ongoing. Conclusions. Rare genetic variants are common causes of the lone atrial fibrillation. TTN gene variant c.13696C > T; p.(Gln4566Ter) is a potential founder variant in the Baltic population. Table 1. Genetic variants in lone AF Gender Age of AF onset Genetic variant Family history Male 53 LMNA: p.(Ser326Thr) AF in mother Male 11 TTN: p.(Trp31854Ter) AF in father Male 30 TTN: p.(GLn4566Ter) AF in uncle Female 45 TTN: p.(GLn4566Ter) Negative Male 37 TTN: p.(GLn4566Ter) AF in father Male 25 TTN: p.(GLn4566Ter) AF in father, maternal and paternal grandmother Female 60 TTN: p.(Arg27414Ter) Sudden cardiac death at the age of 50 in grand father Female 52 TTN: p.(Arg1012Ter) AF in mother

scholarly journals Self-Organization of the Biological Evolution

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 854
Author(s):  
Arber
Keyword(s):  
Genetic Variants ◽  
Molecular Genetic ◽  
Bacterial Genome ◽  
Genetic Research ◽  
Biological Evolution ◽  
Living Organism ◽  
Bacterial Strains ◽  
Different Types ◽  
Set Up ◽  
The One

We report here experiments carried out with nonpathogenic Escherichia coli bacterial strains and their phages. This research yielded interesting insights into their activities, occasionally producing genetic variants of different types. In order to not interfere with the genetic stability of the parental strains involved, we found that the bacteria are genetically equipped to only rarely produce a genetic variant, which may occur by a number of different approaches. On the one hand, the genes of relevance for the production of specific genetic variants are relatively rarely expressed. On the other hand, other gene products act as moderators of the frequencies that produce genetic variants. We call the genes producing genetic variants and those moderating the frequencies of genetic variation “evolution genes”. Their products are generally not required for daily bacterial life. We can, therefore, conclude that the bacterial genome has a duality. Some of the bacterial enzymes involved in biological evolution have become useful tools (e.g., restriction endonucleases) for molecular genetic research involving the genetic set-up of any living organism.

scholarly journals The spectrum of genetic variants of the a- and b-globin clusters in patients with hemoglobinopathies living in the Republic of Dagestan

2020 ◽  
Vol 19 (3) ◽  
pp. 50-53
Author(s):  
S. G. Mann ◽  
E. V. Raikina ◽  
I. M. Yunusova
Keyword(s):  
Genetic Variants ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Research Center ◽  
Federal State ◽  
Endemic Region ◽  
Pediatric Hematology ◽  
Common Genetic Variants ◽  
Abnormal Hemoglobin ◽  
The Republic

Hemoglobinopathies are a group of hereditary hemolytic anemias common in the countries of the Mediterranean, Southeast Asia and Africa, where malaria was previously common. Due to population migration and an increase in the number of mixed marriages, hemoglobinopathies are also relevant to Russia. Among the Russian Federation's subjects, the Republic of Dagestan is the most endemic region for the incidence of hemoglobinopathies. This study aimed to identify the spectrum of mutations in patients with hemoglobinopathies living in the Republic of Dagestan. The research was approved by Independent ethic committee and the academic board of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). Material from 100 patients was sent for molecular genetic research to the Laboratory of Molecular Biology, Federal State Budget Scientific Institution Scientific Research Center for Surgery named after Dmitry Rogachev. Genetic variants of the genes of the a- and b-globin clusters were determined using multiplex ligase-dependent amplification of samples and Sequencing by the Sanger method. Eighteen genetic variants with different frequencies were detected. The mutation frequency of the b-globin cluster was 62.5%, the a-globin cluster was 23.2%, and the variants leading to the appearance of abnormal hemoglobin were 14.3%. The five most common genetic variants among this cohort were also identified: CD8(-AA) and IVSI-110 (G>A), -(a) 3.7 and -(a) 20.5 and the CD6 variant GAG>GTG [Glu>Val] leading to abnormal hemoglobin S.

Rational laboratory diagnostics of primary immunodeficiency disorders

2015 ◽  
Vol 39 (5) ◽  
Author(s):  
Fabian Hauck ◽  
Barbara Bangol ◽  
Mirzokhid Rakhmanov ◽  
Hanns-Georg Klein ◽  
Christoph Klein
Keyword(s):  
Immune System ◽  
Primary Immunodeficiency ◽  
Molecular Genetic ◽  
Diagnostic Methods ◽  
Genetic Diagnostics ◽  
Laboratory Diagnostics ◽  
Human Immune System ◽  
Primary Immunodeficiency Disorders ◽  
Inborn Defects ◽  
Molecular Genetic Diagnostics

Abstract:Primary immunodeficiency disorders (PIDs) are a group of more than 300 conditions associated with inborn defects of different elements of the immune system. First symptoms usually occur during early infancy, but some PIDs may present at first in adolescence or adulthood or after infections with specific pathogens. Typically, the underlying defect results in recurrent and persistent infections that are difficult to treat. However, patients may have a variable and wide set of symptoms ranging from mild to severe and some requiring immediate lifesaving intervention. As PIDs are relatively rare and fundamental immunological knowledge is required to understand them, an accurate diagnosis is often made too late and many patients probably may remain undiagnosed. In this article, we first give an overview on the human immune system and how PIDs are classified according to clinical features and immunological defects. Next, we focus on the possibilities of immunological and molecular genetic diagnostics of PIDs. Benefits and challenges of current diagnostic methods, especially with regard to next-generation sequencing techniques, are discussed.

scholarly journals Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3046
Author(s):  
Marina Pavanello ◽  
Isaac HY Chan ◽  
Amir Ariff ◽  
Paul DP Pharoah ◽  
Simon A. Gayther ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Genetic Variants ◽  
Susceptibility Genes ◽  
Low Grade ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
History Of ◽  
Rare Genetic Variants ◽  
Repair Genes

A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

scholarly journals Characterization of Pathogenic Variants Associated with Hereditary Thrombocytopenias in Families from the Czech Republic

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2343-2343
Author(s):  
Zuzana Vrzalova ◽  
Katerina Stano Kozubik ◽  
Lenka Radova ◽  
Jakub Trizuljak ◽  
Sarka Pospisilova ◽  
...  
Keyword(s):  
Czech Republic ◽  
Genetic Testing ◽  
Genetic Variants ◽  
Dna Analysis ◽  
Molecular Genetic ◽  
Bleeding Disorders ◽  
The Novel ◽  
Molecular Genetic Testing ◽  
The Czech Republic ◽  
Pathogenic Variants

Introduction Inherited thrombocytopenias (IT) are a heterogeneous group of 33 different forms of monogenic disorders caused by molecular defects affecting 40 genes at least. The pathogenic germline variants play an important role in the development and maintenance of hematopoietic system (megakaryopoesis and thrombopoesis). These changes lead to disruption of these processes and are presented as the thrombocytopenia phenotype (low platelet count, blood-examination). However, patients are occasionally misdiagnosed with the immune thrombocytopenia and unsuccessfully treated with steroid therapy and splenectomy. In some patients, accurate diagnosis of IT can only be established based on the results of molecular genetic testing. Furthermore, it has also been shown that some hematological conditions with Mendelian type of hereditability precede the development of hematooncological disease. Patients and Methods DNA samples from peripheral blood or buccal swabs of four unrelated families were isolated. The whole exome sequencing (WES) was performed using the NextSeq 500 Illumina instrument with adequate chemistry and sequencing libraries were prepared according to the SeqCap EZ Human Exome Probes v3 protocol. The generated data were processed using in-house bioinformatics pipelines. The detected pathogenic variants were confirmed by Sanger sequencing. Moreover, the novel variant was analyzed in silico using analytical procedures including protein modelling, too. Germline DNA analysis was performed on all available samples and somatic DNA analysis was done for the oncological patient. Within each family, the obtained pathogenic variants were compared between the individuals with IT phenotype and their disease-free relatives. Results The pathogenic variants were characterized in four families with different forms of IT. Moreover, the additional genetic variants were detected in three of them which predispose to the development of hematological malignancies. In the first family, a novel heterozygous variant c.320C>T; p.(Thr107Met) in TUBB1 gene is probably responsible for essential thrombocytopenia disease because all rare TUBB1 variants until now have been detected in patients with macrothrombocytopenia. The known pathogenic variant c.1402G>T; p.(Val468Phe) in JAK2 gene (10.9% frequency) was identified in a family member suffering from the myeloproliferative disease. In the second family, heterozygous pathogenic variants c.3076C>T; p.(Arg1026Trp) in ITGA2B gene and c.3188G>A; p.(Arg1063His) in JAK2 gene were detected, associated with platelet-type bleeding disorders and hereditary erythrocytosis with megakaryocytic atypia and predisposition for hematological malignancy, respectively. It is known that stomach tumor occurred in patient´s family before. In the third family, heterozygous pathogenic variant c.3493C>T; p.(Arg1165Cys) in MYH9 gene was identified in a patient with macrothrombocytopenia. This variant was associated with Sebastian syndrome, macrothrombocytopenia and granulocyte inclusions and predisposition to kidney failure, hearing loss, and cataracts. In the fourth family, ANKRD26-related thrombocytopenia with predisposition to myeloid malignancy was probably identified in a patient with detected heterogeneous known variant c.-140C>G in 5´ UTR of ANKRD26 gene. Moreover, the novel c.682C>T; p.(Arg228Trp) variant in SYTL3 gene with uncertain significance was detected in this patient. Conclusions The pathogenic variants were detected in unrelated affected families with macrothrombocytopenia, platelet-type bleeding disorders and hereditary erythrocytosis with megakaryocytic atypia, Sebastian syndrome, and ANKRD26-related thrombocytopenia. Moreover, the genetic variants predispose to myeloid malignancy were identified. Molecular genetic testing helped the clinicians to determine the correct diagnosis in these patients. This study was supported by Ministry of Health of the Czech Republic (grant No 16-29447A), and TA CR (TE02000058). Disclosures No relevant conflicts of interest to declare.

scholarly journals Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

2021 ◽  
Author(s):  
Maryem Ouarhache ◽  
Sandrine Marquet ◽  
Amanda Farage Frade ◽  
Ariela Mota Ferreira ◽  
Barbara Ianni ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Chagas Disease ◽  
Genetic Variants ◽  
Interferon Γ ◽  
Loss Of Function ◽  
Inflammatory Cardiomyopathy ◽  
Pathogenic Variants ◽  
Rare Genetic Variants ◽  
Ifn Γ ◽  
Genetically Determined

Abstract Abstract Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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