Research

Orphanet J Rare Dis. 2025 Jul 1;20(1):330. doi: 10.1186/s13023-025-03785-2.

ABSTRACT

BACKGROUND: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by progressive degeneration, immunodeficiency, cancer predisposition, malnutrition, metabolic disorders, and chronic liver disease. The study aims to describe the nutritional status and plasma levels of biomarkers of lipid status, metabolic profile, and liver function of patients with A-T.

RESULTS: A total of 218 patients from 9 Latin American countries were included in the study. The distribution of patients according to nutritional status by age group revealed an over-time increase in the proportion of patients with severe thinness (p = 0.016). High glucose and triglyceride levels were observed in 9.5% and 23.6% of patients, respectively. Total cholesterol was high in 31.7, and 34.0% had abnormal LDL-c levels. In the analysis of paired samples, a progressive increase in aspartate aminotransferase was observed over time.

CONCLUSIONS: The present results are comparable to those of previous studies also showing changes in nutritional status and in lipid, metabolic, and liver profiles over time. These findings confirm a high rate of thinness in patients with A-T and progressive deterioration as the disease progresses, as well as changes in plasma levels of biomarkers of lipid status, metabolic profile, and liver function.

PMID:40597142 | DOI:10.1186/s13023-025-03785-2

BMC Infect Dis. 2025 Jul 1;25(1):873. doi: 10.1186/s12879-025-11106-y.

ABSTRACT

BACKGROUND: Human papillomavirus (HPV) is a prevalent sexually transmitted infection associated with various diseases, including genital warts, recurrent respiratory papillomatosis (RRP), and multiple pre-cancerous diseases and cancers. HPV causes over 90% of cervical cancer cases, the sixth most common cancer among women in China. To support the national plan for accelerating cervical cancer elimination through enhanced HPV vaccination and screening rates, China requires reliable data systems to monitor and evaluate progress effectively.

METHODS: We conducted a scoping review of literature from PubMed and the China National Knowledge Infrastructure databases, supplemented by government documents and news articles from the Internet, spanning April 2012 and July 2023. Our objective was to identify and summarize databases and data systems used for HPV-related real-world evidence generation in China. The identified data systems cover four primary domains: HPV vaccination, HPV screening, HPV-related cervical and non-cervical diseases, and sexual and lifestyle behaviors.

RESULTS: Our review identified a total of 140 articles and 26 databases and data systems. These databases and data systems were categorized into the following reporting areas: HPV vaccination (n = 2), HPV screening (n = 2), HPV-related cervical and non-cervical diseases (n = 21), and sexual and lifestyle behaviors (n = 1). The Immunization Program Information Management System and the regional health care information platform in Ningbo provide HPV vaccination data, while KingMed Diagnostics and the “Two Cancers” Screening Platform track HPV screening at national level. Twenty-one systems were identified for tracking HPV-related cervical and non-cervical diseases, including head and neck cancers, penile lesions, and genital warts; however, no systems were found for anal, vulvar, or vaginal cancers, or RRP. One database, the National Human Immunodeficiency Viruses Epidemiology Database, included information on sexual and lifestyle behaviors. Pilot cities, including Yinzhou, Chengdu, Suzhou, and Lecheng, have implemented population-level data systems capable of identifying information on HPV vaccination, HPV screening, and HPV-related diseases.

CONCLUSIONS: China has made significant progress in addressing HPV-related diseases and prevention, but more integrated and comprehensive data systems are needed to effectively support research, improve interventions, and achieve national and global goals in HPV prevention and cervical cancer elimination.

PMID:40597707 | DOI:10.1186/s12879-025-11106-y

Front Immunol. 2025 Jun 17;16:1605727. doi: 10.3389/fimmu.2025.1605727. eCollection 2025.

ABSTRACT

In contrast to hereditary angioedema (HAE) due to C1-inhibitor deficiency, the detection of pathogenic variants in genes linked to HAE with normal C1 inhibitor levels (HAE-nC1INH) is required for the diagnosis of the corresponding types of the disease. The mainstreaming of genomic technology and the increasing use of next generation sequencing have increased the possibility of an unintentional detection of HAE-nC1INH pathogenic variants and allowed the incidental finding of variants of uncertain significance (VUS) in the relevant genes. Apart from F12 and PLG pathogenic variants, the current level of evidence on the prevalence and penetrance of variants associated with HAE-nC1INH does not support the reporting of their incidental finding. On the other hand, although VUS should not be used in clinical decision-making, further consideration is warranted (a) for VUS found in exon 9 of the F12 gene after a diagnostic genetic analysis of individuals either with or without personal or family history of angioedema, and (b) for VUS found in any of the other genes linked to HAE-nC1INH, after genetic analysis performed in the context of differential diagnosis of angioedema cases. Given the complexity of interpreting, reporting and communicating incidental findings, a close partnership between patients, clinicians, laboratory geneticists and genetic counsellors is essential to optimize the management of these results.

PMID:40599776 | PMC:PMC12208851 | DOI:10.3389/fimmu.2025.1605727

Front Immunol. 2025 Jun 17;16:1596971. doi: 10.3389/fimmu.2025.1596971. eCollection 2025.

ABSTRACT

INTRODUCTION: The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its third edition of the Global Multi-Stakeholders’ Summit, gathering key primary immunodeficiencies (PID) stakeholders and experts to discuss and foment global collaboration.

METHODS: This edition focused on the impact of genomic medicine in PID treatment, the role of digital health, including artificial intelligence, in PID care, and how to anticipate and minimise risks to ensure optimal patient access to care.

RESULTS: These discussions aimed to examine current hurdles and brainstorm feasible solutions and priorities for the PID community in these areas in the next ten years.

DISCUSSION: These discussions led to recommendations for comprehensive approaches to care and access to treatment for PID patients, suggesting actions that will bring the community closer to treatments based on real-world evidence and adjusted to patient’s needs. To accomplish this, collaboration between academia, industry, regulatory authorities, and patients is crucial.

PMID:40599777 | PMC:PMC12209282 | DOI:10.3389/fimmu.2025.1596971

J Allergy Clin Immunol. 2025 Jun 28:S0091-6749(25)00691-8. doi: 10.1016/j.jaci.2025.06.015. Online ahead of print.

ABSTRACT

The rapid growth of artificial intelligence (AI) in healthcare is promising for screening and early diagnosis in settings that heavily rely on professional expertise, such as rare disease (RDs) like Inborn Errors of Immunity (IEI). However, the development of AI algorithms for IEI and other RDs faces important challenges such as data set sizes, availability and harmonization. Similarly, the implementation of AI-based strategies for screening and diagnosis of IEI in real-world scenarios is hampered by multiple factors including stakeholders’ acceptance, ethical and legal constraints, and technological barriers. Consequently, while the body of literature on AI-based solutions for early diagnosis of IEI continues to expand, clinical utility and widespread implementation remains limited. In this review, we provide an up-to-date comprehensive review of current applications and challenges facing AI use for IEI diagnosis and care.

PMID:40588065 | DOI:10.1016/j.jaci.2025.06.015

J Allergy Clin Immunol Glob. 2025 May 26;4(3):100503. doi: 10.1016/j.jacig.2025.100503. eCollection 2025 Aug.

ABSTRACT

Activated PI3K delta syndrome is a rare primary combined immunodeficiency that can present with lymphoma. Genetic testing of patients with atypical lymphoma may reveal an underlying immunodeficiency and improve clinical outcomes.

PMID:40583960 | PMC:PMC12205638 | DOI:10.1016/j.jacig.2025.100503

medRxiv [Preprint]. 2025 Jun 16:2025.06.13.25329369. doi: 10.1101/2025.06.13.25329369.

ABSTRACT

Rare genetic DNA repair deficiency syndromes can lead to immunodeficiency, neurological disorders, and cancer. In the general population, inter-individual variation in DNA repair capacity (DRC) influences susceptibility to cancer and several age-related diseases. Genome wide association studies and functional analyses show that defects in multiple DNA repair pathways jointly increase disease risk, but previous technologies did not permit comprehensive analyses of DNA repair in populations. To overcome these limitations, we used fluorescence multiplex host cell reactivation (FM-HCR) assays that directly quantify DRC across six major DNA repair pathways. We assessed DRC in phytohemagglutinin-stimulated primary lymphocytes from 56 healthy individuals and validated assay reproducibility in 10 individuals with up to five independent blood draws. We furthermore developed generalized analytical pipelines for systematically adjusting for batch effects and both experimental and biological confounders. Our results reveal significant inter-individual variation in DRC for each of 10 reporter assays that measure the efficiency of distinct repair processes. Our data also demonstrate that correlations between the activities of different DNA repair pathways are relatively weak. This finding suggests that each pathway may independently influence susceptibility to the health effects of DNA damage. We furthermore developed a pipeline for analyzing comet repair kinetics and related our new functional data to previously reported comet assay data for the same individuals. Our pioneering analysis underscores the sensitivity of FM-HCR assays for detecting subtle biological differences between individuals and establishes standardized methodologies for population studies. Our findings and open source analytical tools advance precision medicine by enabling comprehensive exploration of genetic, demographic, clinical, and lifestyle factors and supporting targeted interventions to enhance DNA repair and maintain genomic integrity, thereby promoting personalized healthcare and disease prevention.

PMID:40585106 | PMC:PMC12204290 | DOI:10.1101/2025.06.13.25329369

Int J Immunopathol Pharmacol. 2025 Jan-Dec;39:3946320251351138. doi: 10.1177/03946320251351138. Epub 2025 Jun 30.

ABSTRACT

Tyrosine kinase 2 (TYK2) deficiency is a rare primary immunodeficiency disease (PID). Patients carry TYK2 gene mutations and suffer from recurrent infections by intracellular pathogens, including mycobacteria. Delayed diagnosis often hinders timely and effective treatment, resulting in poor prognosis. In this study, we report a newly discovered TYK2 deficiency patient with recurrent pulmonary infections. The patient, a 27-year-old Chinese man with a history of tuberculosis, presented with recurrent cough, phlegm, and purulent sputum. Lung CT scan showed bronchiectasis with concomitant infection. Next-generation sequencing (NGS) identified Mycobacterium gordonae and Mycobacterium chelonae in lung, along with heterozygous c.997G>A&c.10C>T (p.V333M&p.R4C) mutation in TYK2. Further pathogenicity prediction analysis via dbNSFP (v5.1a) suggested the potential pathogenicity of this genetic variant. Additionally, TYK2 mRNA expression in peripheral blood mononuclear cells (PBMCs) also decreased significantly. Following anti-infective treatment, the patient improved and was discharged with regular human immunoglobulin infusion. However, the patient unfortunately succumbed to disease exacerbation in October 2021, 15 months after diagnosis. Furthermore, a literature review was conducted on cases of TYK2 deficiency. Previous studies have identified 24 mutation sites within TYK2 gene, which impair immune function and lead to early-onset recurrent infections. These mutations contribute to clinical heterogeneity, with the most common manifestation being recurrent infections by opportunistic pathogens, particularly mycobacteria. Our discovery of a novel TYK2 mutation expands the gene’s mutation spectrum. Analyzing the characteristics of reported cases enhances understanding of TYK2 deficiency’s clinical manifestations and facilitates early diagnosis of this rare condition.

PMID:40586332 | DOI:10.1177/03946320251351138

medRxiv [Preprint]. 2025 Apr 16:2025.02.20.25322586. doi: 10.1101/2025.02.20.25322586.

ABSTRACT

The European Society for Immunodeficiencies patient registry (ESID-R), established in 1994, is one of the world’s largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R’s structure, data content, and impact. The registry includes 30,628 patient datasets (aged 0-97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings include real-world observations of IEI diagnoses, genetic causes, clinical manifestations, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.

PMID:40568655 | PMC:PMC12191083 | DOI:10.1101/2025.02.20.25322586

Bioinformatics. 2025 Jun 28:btaf378. doi: 10.1093/bioinformatics/btaf378. Online ahead of print.

ABSTRACT

MOTIVATION: Gene network analysis is essential for understanding the complex mechanisms underlying diseases, which often involve disruptions in molecular networks rather than individual genes. Despite the availability of large-scale omics datasets and computational tools for gene network analysis, interpretation of the biological relevance of these extensive networks remains challenging.

RESULT: We propose a novel computational strategy, gene behaviors-based network enrichment analysis, which systematically identifies functional pathways enriched in phenotype-specific gene networks. Our novel method incorporates comprehensive network characteristics, ie, gene expression levels, edge strengths, and structural patterns of edges, to rank genes based on activity and assess pathway enrichment, effectively identifying functional pathways enriched within these networks. Through simulation studies, our strategy demonstrated superior performance compared with that of existing methods in identifying enriched pathways. We applied this strategy to whole-blood RNA-seq data from 1,102 COVID-19 samples provided by the Japan COVID-19 Task Force. The analysis revealed immune disease pathways enriched with COVID-19 severity-specific gene networks, including “Systemic lupus erythematosus” in asymptomatic and severe samples and “Inflammatory bowel disease”, “Primary immunodeficiency” and “Rheumatoid arthritis” in mild samples. Key biomarkers of COVID-19, such as CXCL8, S100A9, and HLA class I genes, have been identified as critical hub genes and the main players within these networks.

AVAILABILITY AND IMPLEMENTATION: Code is available in Figshare (https://doi.org/10.6084/m9.figshare.29093648.v3).

PMID:40580453 | DOI:10.1093/bioinformatics/btaf378