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NPJ Genom Med. 2025 Jan 13;10(1):2. doi: 10.1038/s41525-024-00453-5.

ABSTRACT

Maturation of αβ lineage T cells in the thymus relies on the formation and cell surface expression of a pre-T cell receptor (TCR) complex, composed of TCRβ chain and pre-TCRα (pTCRα) chain heterodimers, giving rise to a diverse T cell repertoire. Genetic aberrations in key molecules involved in T cell development lead to profound T cell immunodeficiency. Definitive genetic diagnosis guides treatment choices and counseling. In this study, we describe the role of whole genome sequencing (WGS) in providing a definitive diagnosis for a child with T cell deficiency, where targeted panel sequencing of SCID genes and whole exome sequencing had failed. A novel homozygous 8kb deletion in PTCRA, encoding pTCRα, was identified. To date, use of WGS remains restricted and for many geographical regions, is clinically unavailable.

PMID:39805825 | DOI:10.1038/s41525-024-00453-5

PLoS Genet. 2025 Jan 13;21(1):e1011328. doi: 10.1371/journal.pgen.1011328. Online ahead of print.

ABSTRACT

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor’s dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.

PMID:39804930 | DOI:10.1371/journal.pgen.1011328

PLoS One. 2025 Jan 13;20(1):e0316797. doi: 10.1371/journal.pone.0316797. eCollection 2025.

ABSTRACT

Primary and secondary antibody deficiencies (PAD and SAD) are amongst the most prevalent immunodeficiency syndromes, often necessitating long-term immune globulin replacement therapy (IRT). Both intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) have demonstrated efficacy in antibody deficiency. Comparative analyses of these two routes of administration are limited to nurse-administered IVIG and home therapy with self-administered SCIG. A third programmatic approach, SCIG administered by nurses in hospital-based outpatient infusion clinics, combines certain advantages of IVIG and home SCIG such as the provision of nursing support and the reduced risk of systemic reactions associated with the subcutaneous route. This cross-sectional study aimed to compare the viability and resource utilization of nurse-administered SCIG with IVIG in patients with antibody deficiency. We hypothesized that nurse-administered SCIG would require a similar amount of infusion clinic time per month as IVIG, despite more frequent dosing, due to shorter individual appointments, while maintaining high patient satisfaction. Information on infusion duration, time in the infusion chair, direct nursing time, and treatment satisfaction using the Life Quality Index was collected. Time measures for each patient were expressed as minutes/4 weeks to account for the more frequent dosing of nurse-administered SCIG compared to IVIG. We determined that the total time, infusion time, and nursing time needed to provide nurse-administered SCIG was comparable to IVIG. The more frequent dosing of SCIG was offset by the shorter times required per infusion. Patients reported favorable treatment satisfaction with both nurse-administered SCIG and IVIG. We conclude that nurse-administered SCIG may be a useful treatment modality for well-selected individuals.

PMID:39804832 | DOI:10.1371/journal.pone.0316797

Turk Arch Pediatr. 2025 Jan 2;60(1):48-56. doi: 10.5152/TurkArchPediatr.2025.24172.

ABSTRACT

Objective: Prolidase deficiency is a metabolic and immunological disorder that is inherited in an autosomal recessive manner. In prolidase deficiency, a broad spectrum of differences is observed in patients, ranging from asymptomatic to multisystem involvement. There is scarce information in the literature on the atypical features and immunophenotypes of this disease. Aim of this study is to present 4 new cases to provide information on the rare features of the disease and to raise awareness. Materials and Methods: This study included 4 female patients with prolidase deficiency. Their demographic, clinical, and immunologic characteristics were obtained from their medical records. Results: There were 4 female patients (P1-P4), with a mean age of 18.5 years (min-max: 10-29) and a mean age of symptom onset of 6.9 years (min-max: 0.04-27). The main presenting complaints of the patients were skin lesions (100%), dysmorphic features (100%), neurodevelopmental delay (100%), frequent infections (100%), and prolonged diarrhea (50%). P2 had diffuse large B-cell lymphoma, resulting in early death. Interestingly, P1 and P2 experienced opportunistic infections such as cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. Three patients (75%) had lymphopenia. Two patients had elevated IgE levels. Lymphocyte subgroup analysis showed an inverted CD4/CD8 ratio in all patients. In patients P1 and P2, the percentages of naive T cells and recent thymic emigrants were reduced, suggesting combined immune deficiency at the time of diagnosis. CD19+ B cells were also low in P1 and P2. Metabolic evaluations revealed low prolidase enzyme activity in P1 and P2. Conclusion: Beyond the well-known classical dermatological findings, the presence of recurrent opportunistic infections, gastrointestinal involvement, malignancy, and flow cytometry findings suggestive of combined immunodeficiency indicate that the diagnosis of prolidase deficiency may be underestimated. Knowing the atypical and rare presentations will facilitate diagnosis and treatment of affected patients.

PMID:39804022 | DOI:10.5152/TurkArchPediatr.2025.24172

J Allergy Clin Immunol Glob. 2024 Nov 26;4(1):100378. doi: 10.1016/j.jacig.2024.100378. eCollection 2025 Feb.

ABSTRACT

Primary or secondary hypogammaglobulinemia is associated with persistent norovirus and Campylobacter infections despite immunoglobulin replacement therapy. Allogeneic hematopoietic cell transplantation for hematologic indications can lead to immune reconstitution by correcting a previously undiagnosed concurrent primary immunodeficiency.

PMID:39802398 | PMC:PMC11719299 | DOI:10.1016/j.jacig.2024.100378

Orphanet J Rare Dis. 2025 Jan 10;20(1):16. doi: 10.1186/s13023-025-03539-0.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare, autosomal dominant disorder causing swelling attacks in various parts of the body, resulting in impacts on health-related quality of life (HRQoL). The symptoms of HAE and its impacts on HRQoL have been well-documented in adults; however, relatively little is known about the experiences of adolescents with HAE. The objective of this study was to use qualitative interviews to investigate how adolescents experience HAE symptoms and how HAE impacts their HRQoL.

METHODS: This was a non-interventional, qualitative study of adolescents with HAE. Participants were recruited via a patient advocacy organization and were eligible to take part in this study if they had a confirmed diagnosis of type I or type II HAE and were currently on prophylactic treatment to prevent HAE attacks. All participants completed a one-to-one, 60-minute, remote interview designed to elicit their experiences of HAE. Interview data were coded and analyzed using NVivo qualitative software.

RESULTS: Twelve adolescents took part in this study. HAE attacks were described as painful and uncomfortable. Attacks varied by trigger, frequency, severity, location, and duration. Participants described ways in which HAE impacted their daily lives, including impacts on physical, social, emotional, and cognitive functioning, in addition to sleep disturbance, school-related impacts, and a need to avoid attack triggers. Impacts on emotional and social functioning were particularly noteworthy, as participants reported having to miss or skip social events, and sometimes withdrawing socially. Since initiating prophylaxis, participants reported the frequency, severity, and duration of attacks had been reduced and their HAE-related impacts had been minimized. Participants were satisfied with their current prophylactic and acute treatments, and expressed a preference for treatments that were effective, convenient, self-administered, and had minimal side effects.

CONCLUSION: Adolescents with HAE reported experiencing a range of symptoms that, when untreated, impacted their HRQoL in ways that are unique from adults. Further, participants reported that effective treatments (prophylactic and acute) inhibited symptoms and HRQoL impacts with minimal treatment burden. Findings from this study suggest that health care providers and clinical investigators should consider the unique HRQoL impacts experienced by adolescents when evaluating treatment benefit.

PMID:39794858 | DOI:10.1186/s13023-025-03539-0

Sci Immunol. 2025 Jan 10;10(103):eadq1697. doi: 10.1126/sciimmunol.adq1697. Epub 2025 Jan 10.

ABSTRACT

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T_H2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage-specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.

PMID:39792639 | DOI:10.1126/sciimmunol.adq1697

Protein Pept Lett. 2025 Jan 8. doi: 10.2174/0109298665350171241204153202. Online ahead of print.

ABSTRACT

BACKGROUND: The role of Zona pellucida glycoprotein 3 (ZP3) is unclear in pancreatic adenocarcinoma (PAAD).

OBJECTIVE: This study aimed to explore the role of ZP3 in PAAD.

METHODS: A comparative analysis of ZP3 gene expression was performed to discern differences between various types of cancer and PAAD, leveraging data sourced from The Cancer Genome Atlas (TCGA). This study aimed to assess the role of ZP3 as a potential diagnostic marker for PAAD. The relationship between ZP3 levels and clinical characteristics, as well as patient outcomes, was scrutinized. Additionally, genomic enrichment analysis was carried out to uncover the underlying regulatory mechanisms associated with ZP3. The study further delved into the association of ZP3 with immune system interactions, checkpoint gene expression, Tumor Mutational Burden (TMB), microsatellite instability (MSI), and tumor stemness index (mRNAsi). The aberrant expression patterns of ZP3 in PAAD cell cultures were confirmed through the application of quantitative reverse transcription PCR (qRT-PCR) techniques.

RESULTS: ZP3 exhibited aberrant expression in both pan-cancer and PAAD. A significant correlation was observed between increased levels of ZP3 expression in PAAD patients and histologic grade (p = 0.026). Elevated ZP3 expression in PAAD was found to be significantly associated with poorer overall survival (p = 0.003), progression-free survival (p = 0.012), and disease-specific survival (p = 0.002). In PAAD, the level of ZP3 gene expression was statistically significant (p < 0.001) and recognized as a key determinant of patient prognosis. ZP3 exhibited associations with various biological pathways, including primary immunodeficiency, oxidative phosphorylation, and other pathways. ZP3 expression demonstrated correlations with immune infiltration, immune checkpoint genes, TMB, MSI, and mRNAsi in PAAD. Moreover, a pronounced negative correlation was detected between ZP3 expression levels and the therapeutic effectiveness of various medications, including selumetinib, bleomycin, FH535, docetaxel, and tanespimycin, within the context of PAAD. Elevated levels of ZP3 were consistently observed in cell line models of PAAD.

CONCLUSION: ZP3 has the potential to serve as a prognostic biomarker and therapeutic target for patients with PAAD.

PMID:39791146 | DOI:10.2174/0109298665350171241204153202

Orphanet J Rare Dis. 2025 Jan 9;20(1):14. doi: 10.1186/s13023-024-03525-y.

ABSTRACT

PURPOSE: Severe combined immunodeficiency (SCID) is a set of rare monogenic inherited diseases that together represent the most severe form of the primary immunodeficiency disease phenotype. Preimplantation genetic testing for monogenic defects (PGT-M) is an effective reproductive technology strategy to prevent disease-causing gene mutations from being transmitted to offspring. The aim of this study was to report the use of PGT-M strategy based on karyomapping in four families to avoid the birth of SCID children.

METHODS: Four couples underwent the PGT-M strategy due to SCID. The strategy of PGT-M started with a biopsy of the trophectoderm cells of embryos, and the whole genome was amplified by multiple replacement amplification (MDA). Then, the single nucleotide polymorphisms (SNPs) in the region upstream and downstream of the mutation site were subsequently identified via karyomapping, and the results were analyzed via SNPs linkage analysis. The aneuploids of the embryos were identified simultaneously. Finally, prenatal amniocentesis was used to verify the validity of the PGT-M results.

RESULTS: We identified three novel variants (case1: IL2RG c.720_726delGAGCCAC; case 3: RAG2 c.770 C > T; and case 4: LIG4 c.1347 A > T). All four couples with SCID pathogenic gene mutations were subjected to karyomapping linkage analysis, and embryos with the pathogenic gene mutation were successfully identified. Euploid blastocysts without pathogenic alleles were transplanted, and healthy offspring were ultimately born. Prenatal diagnosis also confirmed the validity of our results.

CONCLUSION: This study revealed that karyomapping is an efficient approach for identifying SCID. Through PGT-M with karyomapping linkage analysis, healthy babies were born to families carrying mutations in the SCID pathogenic gene.

PMID:39789600 | DOI:10.1186/s13023-024-03525-y

Scand J Immunol. 2025 Jan;101(1):e13431. doi: 10.1111/sji.13431.

ABSTRACT

This study retrospectively analyzed the outcomes of 61 pediatric patients with inborn errors of immunity (IEI) who underwent hematopoietic stem cell transplantation (HSCT) between 2011 and 2023. Patients were categorized into primary immunodeficiency disorders (PIDD), primary immune dysregulation disorders (PIRD), and congenital defects of phagocyte number or function (CDP). Median ages at diagnosis and HSCT were 9 and 30 months, respectively. With a median follow-up of 51 months, the overall survival (OS) was 70%, with a 100-day post-transplant OS of 80%. Transplant-related mortality (TRM) was 29%, with rates of 42%, 22.5%, and 27% for PIRD, PIDD, and CDP, respectively. This study highlights the importance of early diagnosis and HSCT in improving survival for IEI patients, while also emphasizing the need for continuous improvements in transplant protocols to minimize TRM and enhance quality of life.

PMID:39781591 | DOI:10.1111/sji.13431