Background: Copy Number Variation (CNV) is associated with numerous complex diseases, yet their pathogenicity assessment remains heavily dependent on manual expert review, a process that is cumbersome and time-consuming. Although a variety of automated tools for CNV pathogenicity prediction have been developed, systematic assessments of their performance and clinical generalizability under the five-category classification framework defined by ACMG standards remain scarce. Methods: This study constructed an expert-reviewed CNV benchmark dataset. Under the ACMG five-category system, it systematically compared the classification prediction capabilities of five prediction tools across both deletion and duplication CNV samples. Furthermore, it assessed their applicability in real clinical samples and evaluated potential biases towards specific variations. Results: The study indicates that different tools exhibit performance variations and specialised strengths across different classification tasks, yet overall capability in distinguishing clinical risk boundaries across the five categories remains inadequate. Among these, AnnotSV demonstrated outstanding performance in predicting pathogenic samples, achieving accuracy rates of 95.16% and 86.39% on the deletion and duplication benchmark datasets respectively. ClassifyCNV demonstrated optimal performance in variant of uncertain significance classification with an accuracy of 95.33%. Furthermore, all models exhibited significantly superior five-category discrimination capabilities for deletion samples compared with duplication samples, revealing pronounced performance biases across variant types. Conclusion: Current automated CNV prediction tools demonstrate higher discriminatory capacity for deletion variants than for duplications; however, they remain insufficient to fully replace manual expert review within the ACMG five-category framework. Further optimisation using multicentre, consistently curated clinical gold-standard datasets is required to improve their reliability and clinical applicability.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder primarily caused by pathogenic variants in PKD1 and PKD2. Although molecular testing has revolutionized diagnosis, variability persists in testing strategies and diagnostic yields. This review aims to evaluate molecular genetic techniques used in ADPKD diagnosis and summarize evidence on their diagnostic performance. Method: Following a predefined protocol and PRISMA 2020 guidelines, PubMed, Scopus, and Web of Science were searched for studies published between January 2015 and August 2025. Eligible studies included ≥ 30 clinically diagnosed ADPKD participants and reported patient-level diagnostic data. Two investigators independently extracted information on testing methods, diagnostic yield, and identified genes. Results: From 23,718 records, 20 studies met inclusion criteria, with sample sizes ranging from 32 to 634 participants. Diagnostic methods included Sanger sequencing (SS), multiplex ligand-probe amplification (MLPA), long-range PCR (LR-PCR), targeted next-generation sequencing (NGS) panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS). Detection rates ranged from 61% (LR-PCR) to 92% (targeted NGS). PKD1 and PKD2 variants accounted for 79.9% and 15.9% of cases, respectively. Additional variants were identified in GANAB, HNF1B, IFT140, PRKCSH, and PKHD1. Conclusion: Targeted NGS panels provided the highest diagnostic accuracy and cost-effectiveness for ADPKD. Complementary use of MLPA and LR-PCR improved detection of complex variants. Further optimization of sequencing workflows and variant interpretation will enhance diagnostic precision and clinical application. This review provides an evidence-based foundation for current diagnostic practices in ADPKD.

Adams-Oliver Syndrome Type 4 (AOS4) is a rare autosomal recessive disorder primarily characterized by aplasia cutis congenita and cranial defects. Pathogenic variants in several genes, including DOCK6, ARHGAP31, EOGT, RBPJ, DLL4, and NOTCH1, have been implicated in the etiology of AOS. In this study, we identified two novel compound heterozygous mutations in the EOGT gene (c.961 C > T, p.R321C and c.1115 G > A, p.R372Q) in a patient with AOS4. Both variants were predicted to be deleterious through structural and computational analyses, and these mutations are likely to impair enzymatic function without affecting subcellular localization. Given the established role of EOGT in O-GlcNAcylation and its regulatory relationship with Notch signaling, we further proposed that these mutations may disrupt Notch pathway activity through aberrant modification of Notch receptors, thereby contributing to the defective skin development observed in AOS4. These findings highlight a potential pathogenic mechanism for AOS4 and underscore the critical role of EOGT-mediated glycosylation in human development.

In patients with primary immune thrombocytopenia (ITP), the risk of thrombosis associated with thrombopoietin receptor agonists (TPO-RAs) remains debated. This study compared the thrombosis occurrence in ITP patients before and after the launch of TPO-RAs in China, to explore the relationship between TPO-RAs and thrombosis in ITP patients. Data from 2005 to 2017 were obtained from an article published by the Blood Disease Hospital, Chinese Academy of Medical Sciences in 2018. The present study included 1915 hospitalized patients in the same center from January 2018 to February 2025. Among these, thrombosis events occurred in 33 cases (1.72%). The incidence of arterial thrombosis was higher than that of venous thrombosis. Male gender, age over 40 years old, hypertension, diabetes, smoking, and TPO-RAs were associated with thrombosis. Neither platelet count nor stage of ITP showed a significant effect on thrombosis risk. Although the utilization rate of TPO-RAs increased significantly after 2018, no corresponding significant change in thrombosis incidence was observed. These findings suggest that thrombosis in ITP patients results from the interplay of multiple risk factors. While the widespread use of TPO-RAs does not appear to increase the overall risk of thrombosis in ITP patients, caution is still advised when administering these agents to patients with pre-existing thrombosis risk factors.

Objective: To investigate the associations between urinary and serum metal levels and neurodegenerative diseases (NGDs) as well as all-cause mortality, and identify research trends through bibliometric. Methods: This study first analyzed data from a large-scale national cross-sectional survey (2005–2018) involving 6288 participants. Multivariable regression models were used to assess the associations of urinary metals (Ba, Cd, Co, Cs, Mo, Pb, Sb, Tl, W) and serum metals (Fe, Cd, Pb, Hg) with the risk of neurodegenerative diseases (NGDs) and all-cause mortality. Subsequently, a bibliometric analysis was conducted on literature pertaining to "metals" and "NGDs" retrieved from the Web of Science Core Collection to identify research trends and key underlying mechanisms. Results: Epidemiological analyses revealed significant associations between several metals—such as Cd, Cs, Mo, Hg, and Pb—and either NGDs risk or all-cause mortality, with some exhibiting nonlinear patterns (e.g. L-shaped or inverted U-shaped relationships). Subsequent bibliometric analysis of 34,313 publications identified "iron" as a central hub keyword linking "metal exposure" to "neurodegenerative diseases". Mechanisms related to Fe—including "oxidative stress" and "lipid peroxidation"—emerged as research hotspot keywords. Notably, the cluster labeled "ferroptosis" demonstrated substantial scale in co-citation clustering. Research trajectories have evolved from broad pathological observations toward molecular-level investigations of the NLRP3 inflammasome, glutathione peroxidase 4 (GPX4), ultimately converged on the ferroptosis pathway. Conclusion: Exposure to multiple metals is significantly associated with the risk and prognosis of NGDs. Integrated bibliometric evidence highlights ferroptosis as the central mechanism bridging metal dyshomeostasis and neuronal injury, offering a cohesive evidence chain from population data to mechanistic insights.

Type 2 diabetes (T2D) is a metabolic disorder characterised by hyperglycaemia, reduced insulin secretion, and increased insulin resistance, yet its mechanisms are not fully understood. While genetic predisposition contributes to the variable disease presentation across different ethnic populations, it does not fully explain the burden of T2D. Global 5-methylcytosine (5-mC) has emerged as an important regulator of gene expression, influencing disease pathogenesis through interactions with environmental factors. In parallel, circulating exosomes have attracted significant attention in research due to their role in mediating cell-to-cell communication and their capability to transport bioactive molecules, including methylated genomic DNA, that influence gene expression and metabolic pathways. The combined contribution of 5-mC and circulating exosome concentration to T2D pathogenesis in African populations remains poorly understood. A South African community case-control study of 40 T2D cases and 40 healthy controls quantified exosomes and 5-mC using their corresponding enzyme-linked immunosorbent assay. Associations of variables with T2D were evaluated using linear and logistic regression models. Serum exosome concentrations were positively correlated with global 5-mC (r = 0.269, p = 0.016). Global 5-mC levels were positively associated with triglycerides (r = 0.232, p = 0.038) and inversely correlated with weight in the diabetic group (r = -0.342, p = 0.038), while exosomes showed a sex-specific inverse association with diastolic blood pressure in males (r = -0.585, p = 0.028). However, neither biomarker independently predicted T2D after adjustment for confounders. These findings suggest a modest interplay between epigenetic modification and exosome signalling, warranting further investigation in larger studies.

Introduction:Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder that is characterized by microcephaly and neurological and renal abnormalities. Ten types of GAMOS exist based on the underlying implicated gene. The purpose of this study was to investigate the phenotypic and genotypic spectrum of GAMOS in Kuwait. Methods:We queried the Kuwait Medical Genetic Center database for subjects with neuro-renal or neurological phenotypes and pathogenic variants in any of the ten known genes associated with GAMOS. Results:We identified eight subjects from five unrelated families with biallelic pathogenic WDR73 variants and a diagnosis of GAMOS type 1 (GAMOS1). All subjects had global developmental delay, microcephaly, tone abnormalities and impaired activities of daily living. Renal features were observed in more than half of the subjects (5/8 subjects) and included proteinuria, nephrotic syndrome, and end-stage renal disease (ESRD). More than half of the subjects (5/8 subjects) died by 5–10 due to ESRD, including one of which who died due to unknown cause while the rest (ages 3–5 years) are still living with no renal features. Two possible founder variants were identified, including c.287 G > A;p.Arg96Lys in three unrelated families of Kuwaiti, Iraqi, and/or Syrian ancestry, and c.767 G > A;p.Arg256Gln in two unrelated families of Kuwaiti or Syrian ancestry. Conclusion:GAMOS1 is the most prevalent form of GAMOS in Kuwait, likely due to the presence of two WDR73 regional founder variants. These findings contribute to the global understanding of GAMOS and highlight the important contribution of regional genetic studies in diverse populations to rare disease research.

Background:The TTN gene encodes titin, a key structural protein of the sarcomere. Variants in TTN are frequently identified in genetic testing, but their clinical interpretation remains challenging due to their high prevalence in the general population and frequent classification as variants of uncertain significance (VUS). Toe walking is often considered idiopathic; however, emerging evidence suggests a potential genetic contribution. Objective:To provide a descriptive analysis of TTN variants in children presenting with persistent toe walking, using a region-based approach to explore variant distribution and associated clinical features. Methods:This retrospective study included children with persistent toe walking following exclusion of known neurological, neuromuscular, and orthopedic causes. All patients underwent standardized clinical assessment and targeted next-generation sequencing using a 49-gene panel. TTN variants were grouped into predefined cDNA intervals (c.1–c.9000). Clinical and genetic data were analyzed descriptively. Results:Fifty-five patients carrying 43 TTN variants were included (mean age 7.3 years; 71% male). Variants were unevenly distributed, with clustering in the c.1001–2000 (22.4%) and c.3001–4000 (19.0%) regions. All variants were classified as VUS. A consistent clinical phenotype was observed across groups, including persistent toe walking, reduced ankle dorsiflexion, and a frequent positive foot drop test. Group-specific differences were noted but remained inconsistent and descriptive. Conclusions: TTN variants in children with toe walking show heterogeneous distribution but a largely consistent clinical presentation. No clear genotype–phenotype correlation was identified. These findings highlight the need for cautious interpretation of TTN VUS and further studies to clarify their clinical significance.