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| [Paper Type: Novel mutation and VUS] AND [Author: Reid, Brenda] (3) | 26 Mar 2025 |
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- OPEN ACCESSBackground: 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 1 mutation have been reported. Subsequently, whole genome sequencing revealed a novel second heterozygous missense variant, H945D (c.2833G>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.
- OPEN ACCESSIntroduction: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta (PIK3CD) is one part of a heterodimer forming the enzyme phosphoinositide 3-kinase (PI3K), found primarily in leukocytes. PIK3CD generates phosphatidyl-inositol 3,4,5-trisphosphate (PIP3), and is involved in cell growth, survival, proliferation, motility, and morphology. An increasing number of patients have been described with heterozygous PIK3CD gain-of-function (GOF) mutations, leading to combined immunodeficiency with both B- and T-cell dysfunction. Patients suffer recurrent respiratory infections, often associated with bronchiectasis and ear and sinus damage, as well as severe recurrent or persistent infections by herpesviruses, including EBV-induced lymphoproliferation.Aim: To present the clinical phenotypic variability of a novel PI3KCD mutation within a family.Methods: Patient information was collected prospectively and retrospectively from medical records. Comprehensive immune work up, genetic, and signaling evaluation was performed.Results: We describe here 2 patients, daughter and mother, with heterozygous PIK3CD mutation identified by whole exome sequencing and Sanger confirmation. The child was screen-positive by newborn screening for severe combined immunodeficiency (SCID). Cellular assays revealed an increase in the baseline phosphorylation of T cells in the patient. Furthermore, both patients had hyper-activation of the catalytic domain, resulting in increased phosphorylation of AKT upon activation.Discussion: GOF mutations affecting the PIK3CD gene are associated with an increased risk for lymphoproliferation leading to Activated PIK3-delta syndrome (APDS). The clinical course of APDS is highly variable, ranging from combined immunodeficiency with recurrent infections, autoimmune complications, and requiring stem cell transplantation, through isolated antibody deficiency, to asymptomatic adults. Our patient is the first to be identified by newborn screening for SCID. Surprisingly, the clinical course has so far been unremarkable, as well, the mother appears to be completely asymptomatic. Nevertheless, the persistent lymphopenia indicates PIK3CD dysfunction. Because of the wide gap between laboratory findings and clinical manifestations, this kindred poses both a diagnostic as well treatment challenge.Statement of novelty: We report here a novel PIK3CD mutation diagnosed due to abnormal newborn screen for SCID.
- OPEN ACCESS
- Luis Murguia-Favela,
- Vy Hong-Diep Kim,
- Julia Upton,
- Paul Thorner,
- Brenda Reid,
- Adelle Atkinson, and
- Eyal Grunebaum
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency caused by inherited defects in the FOXP3 gene that impair regulatory T cells. IPEX syndrome can be cured by hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD); however, the best conditioning prior to HSCT for IPEX syndrome is not known.Here we report on a patient suffering from IPEX syndrome, including immune-mediated colitis and membranous nephropathy, without polyendocrinopathy, caused by a novel mutation in the Forkhead domain of the FOXP3 gene. The patient's symptoms resolved following MUD HSCT after myeloablative conditioning performed at 16 months of age. The patient is clinically well, 3 years after HSCT, with robust immune reconstitution and fully engrafted. The lack of extensive autoimmune damage might have contributed to the patient's favourable outcome following MUD HSCT with myeloablative conditioning.Statement of novelty: We describe a novel mutation in the FOXP3 gene causing IPEX syndrome and the correction of IPEX syndrome with bone marrow transplant from a HLA-matched unrelated donor following myeloablative conditioning.
