scholarly journals Functional genetics in inborn errors of immunity

2021 ◽  
pp. FRD11
Author(s):  
Emma Rey-Jurado ◽  
María Cecilia Poli
Keyword(s):  
Primary Immunodeficiencies ◽  
Genetic Defects ◽  
Potential Candidate ◽  
Functional Validation ◽  
Inborn Errors ◽  
Susceptibility To Infection ◽  
Inborn Errors Of Immunity ◽  
Genes Encoding ◽  
Generation Sequencing ◽  
Increased Susceptibility

Inborn errors of immunity are genetic defects of the immune system, causing increased susceptibility to infection, autoinflammation, autoimmunity and immune dysregulation. Next-generation sequencing has enabled exponential identification of novel inborn errors of immunity due to mutations in genes encoding for proteins that participate in the immune response. However, genomic sequencing often yields multiple variants in potential candidate genes, hence functional validation of these genetic defects becomes paramount to achieve diagnosis and discovery. Genome-editing technologies such as CRISPR-Cas9 have allowed exponential advances on discovery of new primary immunodeficiencies, enabling appropriate diagnosis and treatment. This review summarizes the heterogeneous clinical presentation of primary immunodeficiencies and contextualizes the rationale for functional validation studies to achieve diagnosis and discovery, subsequently leading to the application of directed therapies.

scholarly journals Treatment of immune-mediated cytopenias in patients with primary immunodeficiencies and immune regulatory disorders (PIRDs)

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 673-679
Author(s):  
Markus G. Seidel
Keyword(s):  
Lupus Erythematosus ◽  
Bone Marrow Failure ◽  
Primary Immunodeficiencies ◽  
Definitive Treatment ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Rheumatologic Diseases ◽  
Inborn Errors Of Immunity ◽  
Immune Mediated ◽  
Regulatory Disorders

Abstract Severe immune cytopenias (SICs) are rare acquired conditions characterized by immune-mediated blood cell destruction. They may necessitate emergency medical management and long-term immunosuppressive therapy, strongly compromising the quality of life. The initial diagnostic workup involves excluding malignancies, congenital cytopenias, bone marrow failure syndromes, infections, and rheumatologic diseases such as systemic lupus erythematosus. Causal factors for SIC such as primary immunodeficiencies or immune regulatory disorders, which are referred to as inborn errors of immunity (IEIs), should be diagnosed as early as possible to allow the initiation of a targeted therapy and avoid multiple lines of ineffective treatment. Ideally, this therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway; it can also act indirectly, enhancing a countermechanism against the disease-causing defect. Ultimately, the diagnosis of an underling IEI in patients with refractory SIC may lead to evaluation for hematopoietic stem cell transplantation or gene therapy as a definitive treatment. Interdisciplinary care is highly recommended in this complex patient cohort. This case-based educational review supports decision making for patients with immune-mediated cytopenias and suspected inborn errors of immunity.

scholarly journals Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives

2021 ◽  
Author(s):  
Emil E. Vorsteveld ◽  
Alexander Hoischen ◽  
Caspar I. van der Made
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Primary Immunodeficiencies ◽  
Next Generation ◽  
Inborn Errors ◽  
New Genes ◽  
Whole Exome ◽  
Generation Sequencing

AbstractPrimary immunodeficiencies comprise a group of inborn errors of immunity that display significant clinical and genetic heterogeneity. Next-generation sequencing techniques and predominantly whole exome sequencing have revolutionized the understanding of the genetic and molecular basis of genetic diseases, thereby also leading to a sharp increase in the discovery of new genes associated with primary immunodeficiencies. In this review, we discuss the current diagnostic yield of this generic diagnostic approach by evaluating the studies that have employed next-generation sequencing techniques in cohorts of patients with primary immunodeficiencies. The average diagnostic yield for primary immunodeficiencies is determined to be 29% (range 10–79%) and 38% specifically for whole-exome sequencing (range 15–70%). The significant variation between studies is mainly the result of differences in clinical characteristics of the studied cohorts but is also influenced by varying sequencing approaches and (in silico) gene panel selection. We further discuss other factors contributing to the relatively low yield, including the inherent limitations of whole-exome sequencing, challenges in the interpretation of novel candidate genetic variants, and promises of exploring the non-coding part of the genome. We propose strategies to improve the diagnostic yield leading the way towards expanded personalized treatment in PIDs.

Approach to genetic diagnosis of inborn errors of immunity through next-generation sequencing

2021 ◽  
Vol 137 ◽  
pp. 57-66
Author(s):  
Esmat Karimi ◽  
Fatemeh Mahmoudian ◽  
Saul O. Lugo Reyes ◽  
Umair Ahmed Bargir ◽  
Manisha Madkaikar ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Next Generation ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Generation Sequencing

scholarly journals AWARENESS OF DOCTORS AND PATIENTS ABOUT INBORN ERRORS OF IMMUNITY

2020 ◽  
Vol 11 (4) ◽  
pp. 16-21
Author(s):  
E.V. Zaitseva ◽  
Keyword(s):  
Quantitative Research ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
The Body ◽  
Primary Immunodeficiencies ◽  
Malignant Neoplasms ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Child Patient ◽  
Primary Care Doctors

The immune system protects the body. When defenses are compromised, people with hereditary immunological disorders become vulnerable to many life-threatening infections. Inborn errors of immunity (primary immunodeficiencies), manifested in patients in increased susceptibility to infectious diseases, autoimmune diseases, allergies, and malignant neoplasms. Today, this group of diseases is still considered quite rare. However, the development of diagnostic technologies expands the list of nosologies associated with inborn errors of immunity. Neonatal screening for inborn errors of immunity could solve many of the problems of these patients, but the procedure is not carried out in the Russian Federation. Therefore, diagnostics based on an analysis of the clinical manifestations of diseases. In most cases, the disease is diagnosed in early childhood. Here, the role of both the parents of the child-patient and the medical staff is important. The health and life of the child depends on their awareness of the disease, methods of diagnosis, treatment. This group of diseases is chronic, under an hour, severe. In the absence of timely diagnosis and proper therapy, it can be fatal. The article describes the experience of applied quantitative research conducted by the method of questioning patients with primary immunodeficiencies (parents of underage patients), about their disease, methods of treatment, problems arising in the long-term struggle with this complex disease. The author notes that patients and primary care doctors or general practitioners are poorly informed about diseases associated with primary immunodeficiencies. It is concluded that it is necessary to increase the informational medical culture of the population, especially the young, as participants in the interaction "doctor-patient" and representatives of the interests of minor children-patients with inborn errors of immunity.

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

2020 ◽  
Vol 98 (3) ◽  
pp. 231-239
Author(s):  
Evgeny N. Suspitsin ◽  
Marina N. Guseva ◽  
Mikhail M. Kostik ◽  
Anna P. Sokolenko ◽  
Nataliya V. Skripchenko ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Clinical Suspicion ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Next Generation Sequencing Analysis ◽  
Generation Sequencing

scholarly journals Recent advances in primary immunodeficiency: from molecular diagnosis to treatment

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 194 ◽  
Author(s):  
Giorgia Bucciol ◽  
Isabelle Meyts
Keyword(s):  
Gene Therapy ◽  
Primary Immunodeficiency ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Technological Advances ◽  
Fast Pace ◽  
Recent Developments ◽  
Generation Sequencing ◽  
Review Current ◽  
Diagnostics And Therapy

The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy.

scholarly journals Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

2020 ◽  
Vol 40 (1) ◽  
pp. 24-64 ◽  
Author(s):  
Stuart G. Tangye ◽  
Waleed Al-Herz ◽  
Aziz Bousfiha ◽  
Talal Chatila ◽  
Charlotte Cunningham-Rundles ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rapid Identification ◽  
Expert Committee ◽  
International Union ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Immunological Mechanisms ◽  
Gene Defects ◽  
Generation Sequencing

Abstract We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

scholarly journals The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

2021 ◽  
Vol 41 (3) ◽  
pp. 666-679 ◽  
Author(s):  
Stuart G. Tangye ◽  
Waleed Al-Herz ◽  
Aziz Bousfiha ◽  
Charlotte Cunningham-Rundles ◽  
Jose Luis Franco ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Primary Immunodeficiencies ◽  
Expert Committee ◽  
International Union ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Gene Defects ◽  
Immune Defects

AbstractThe most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

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