A Homozygous RAG1 Gene Mutation in a Case of Combined Immunodeficiency: Clinical, Molecular, and Computational Analysis

2019 ◽  
Vol 84 (6) ◽  
pp. 272-278
Author(s):  
Soukaina Essadssi ◽  
Ibtihal Benhsaien ◽  
Amina Bakhchane ◽  
Hicham Charoute ◽  
Houria Abdelghaffar ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Homozygous Mutation ◽  
Combined Immunodeficiency ◽  
Cmv Infection ◽  
Rag1 Gene ◽  
Whole Exome ◽  
Immunological Phenotype ◽  
Recombination Activating Gene ◽  
Genetic Profiles

<b><i>Background:</i></b> The recombination-activating gene 1 and 2 (RAG1/RAG2) proteins are essential to initiate the V(D)J recombination process, the result is a diverse repertoire of antigen receptor genes and the establishment of the adaptive immunity. RAG1 mutations can lead to multiple forms of combined immunodeficiency. <b><i>Methods:</i></b> In this report, whole exome sequencing was performed in a Moroccan child suffering from combined immunodeficiency, with T and B lymphopenia, autoimmune hemolytic anemia, and cytomegalovirus (CMV) infection. <b><i>Results:</i></b> After filtering data and Sanger sequencing validation, one homozygous mutation c.2446G&#x3e;A (p.Gly816Arg) was identified in the RAG1 gene. <b><i>Conclusion:</i></b> This finding expands the spectrum of immunological and genetic profiles linked to RAG1 mutation, it also illustrates the necessity to consider RAG1 immunodeficiency in the presence of autoimmune hemolytic anemia and CMV infection, even assuming the immunological phenotype appears more or less normal.

Combined Immunodeficiency, Hemolytic Anemia, and Growth Retardation Secondary to a Homozygous Mutation in the NHEJ1 Gene

2020 ◽  
Vol 42 (4) ◽  
pp. 333-335
Author(s):  
Reem Al-Marhoobi ◽  
Musleh Al-Musalhi ◽  
Shafiq-Ur-Rehman Naseem ◽  
Yasser Wali ◽  
Abeer Alsayegh ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Growth Retardation ◽  
Homozygous Mutation ◽  
Combined Immunodeficiency

Fatal Warm Autoimmune Hemolytic Anemia Resulting From IgM Autoagglutinins in an Infant With Severe Combined Immunodeficiency

2001 ◽  
Vol 23 (4) ◽  
pp. 250-252 ◽  
Author(s):  
Anna Nowak-Wegrzyn ◽  
Karen E. King ◽  
R. Sue Shirey ◽  
Allen R. Chen ◽  
Colleen McDonough ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency

Identification of a Novel RAG1 Hypomorphic Mutation in a Child Presenting with Disseminated Vaccine-Strain Varicella.

2021 ◽  
Author(s):  
Mei Xu ◽  
Brenda Elaine Reid ◽  
Chaim M Roifman
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Vaccine Strain ◽  
Clinical Presentation ◽  
Missense Variant ◽  
Whole Genome ◽  
Hematopoietic Stem ◽  
Rag1 Gene ◽  
Whole Exome ◽  
Recombination Activating Gene

Background: Recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) encode unique lymphocyte endonuclease proteins that are crucial in T and B cell development through V(D)J recombination. RAG1 gene defects lead to variable phenotypes, ranging from immunocompetent to severe combined immunodeficiency (SCID). Curative therapy for severe manifestations can be achieved through hematopoietic stem cell transplantation (HSCT). Advances in genomic sequencing have led to the discovery of new variants and it is recognized that the level of recombinase activity correlates with disease severity. Aim: To report the clinical presentation, immunological work-up, decision process to undergo HSCT, and confirmatory genetic diagnosis in a patient who was well until her initial presentation with disseminated vaccine-strain varicella. Methods: Clinical data was gathered through retrospective chart review. Immunological investigations, targeted gene sequencing, and thymic biopsy results were reviewed. Further genetic analysis, including whole exome and whole genome sequencing was performed. Results: Whole exome sequencing identified a single missense mutation in RAG1, R474C (c.1420C>T), which would not account for the clinical presentation. Healthy individuals with only one mutation have been reported. Subsequently, whole genome sequencing revealed a novel second heterozygous missense variant, H945D (c.2833 G>T) in the RAG1 gene. Conclusion: Hypomorphic RAG1 mutations with residual activity have a diverse phenotypic expression. Identifying and understanding the implications of these mutations is crucial for disease prognostication and tailoring management. Statement of Novelty: We present a novel RAG1 missense variant, with likely complete or partial loss of function, in a patient with significant impairment in cellular immunity.

Primary immunodeficiencies (PIDs) presenting with cytopenias

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 139-143 ◽  
Author(s):  
Luigi D. Notarangelo
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Hematopoietic Cell Transplantation ◽  
Primary Immunodeficiencies ◽  
Combined Immunodeficiency ◽  
T And B Cells ◽  
Full Resolution ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias ◽  
Common Variable

Abstract Autoimmune manifestations are increasingly being recognized as a component of several forms of primary immunodeficiencies (PID). Defects in purging of self-reactive T and B cells, impaired Fas-mediated apoptosis, abnormalities in development and/or function of regulatory T cells, and persistence of immune activation as a result of inability to clear infections have been shown to account for this association. Among autoimmune manifestations in patients with PID, cytopenias are particularly common. Up to 80% of patients with autoimmune lymphoproliferative syndrome (ALPS) have autoantibodies, and autoimmune hemolytic anemia and immune thrombocytopenia have been reported in 23% and 51% of ALPS patients, and may even mark the onset of the disease. ALPS-associated cytopenias are often refractory to conventional treatment and represent a therapeutic challenge. Autoimmune manifestations occur in 22% to 48% of patients with common variable immunodeficiencies (CVIDs), and are more frequent among CVID patients with splenomegaly and granulomatous disease. Finally, autoimmune cytopenias have been reported also in patients with combined immunodeficiency. In particular, autoimmune hemolytic anemia is very common among infants with nucleoside phosphorylase deficiency. While immune suppression may be beneficial in these cases, full resolution of the autoimmune manifestations ultimately depends on immune reconstitution, which is typically provided by hematopoietic cell transplantation.

A newly found homozygous mutation in recombination activating gene 1 in a patient with leaky severe combined immunodeficiency disorder

2019 ◽  
Vol 46 (6) ◽  
pp. 6571-6575
Author(s):  
Fereshteh Salari ◽  
Fatemeh Zaremehrjardi ◽  
Saba Arshi ◽  
Mohammad Hassan Bemanian ◽  
Morteza Fallahpour ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Homozygous Mutation ◽  
Combined Immunodeficiency ◽  
Immunodeficiency Disorder ◽  
Recombination Activating Gene

scholarly journals Loss of human ICOSL results in combined immunodeficiency

2018 ◽  
Vol 215 (12) ◽  
pp. 3151-3164 ◽  
Author(s):  
Lucie Roussel ◽  
Marija Landekic ◽  
Makan Golizeh ◽  
Christina Gavino ◽  
Ming-Chao Zhong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
B Cell ◽  
Viral Infections ◽  
Experimental Models ◽  
Homozygous Mutation ◽  
Combined Immunodeficiency ◽  
Naturally Occurring ◽  
Whole Exome ◽  
Surface Localization

Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C&gt;G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.

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