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PubMed2026

Discovery and validation of GNA12circle as a first-trimester plasma eccDNA marker for early-onset preeclampsia.

BACKGROUND: Early-onset preeclampsia (EOPE) is a major cause of maternal and perinatal morbidity and is characterized by placental dysfunction, systemic endothelial injury, and hypertensive vascular stress. Because hypertensive disorders of pregnancy may also signal later maternal cardiovascular and cerebrovascular vulnerability, effective biomarkers for first-trimester risk assessment remain clinically important. Extrachromosomal circular DNA (eccDNA), a stable form of circulating cell-free DNA, has emerged as a potential source of disease-associated biomarkers. This study aimed to characterize first-trimester plasma eccDNA alterations associated with subsequent EOPE and to identify and validate a candidate circulating eccDNA marker for early risk assessment. METHODS: A two-stage nested case-control study was conducted within a prospective birth cohort. In the discovery stage, plasma samples collected at 11-13 weeks of gestation from 5 women who subsequently developed EOPE and 5 matched normotensive controls were profiled by Circle-Seq to characterize genome-wide eccDNA alterations. Candidate eccDNAs were prioritized through differential abundance analysis and were further confirmed by outward PCR and Sanger sequencing. In the validation stage, the candidate selected marker was quantified by junction-specific qPCR in an independent cohort of 109 EOPE cases and 109 controls. Its potential predictive value was further evaluated alone and in combination with routine first-trimester clinical variables. RESULTS: In the exploratory discovery analysis, 410 nominally differentially abundant candidate eccDNAs were identified as a hypothesis-generating pool. Among these, GNA12circle (chr7:2876332-2,876,692) was prioritized and experimentally validated at the circular junction. In the independent validation cohort, plasma GNA12circle levels were significantly higher in women who later developed EOPE than in controls. When combined with routine first-trimester variables, GNA12circle improved predictive performance. The RF model showed the best overall cross-validated performance among the evaluated classifiers, with a mean held-out test-fold AUC of 0.843. CONCLUSION: First-trimester plasma eccDNA profiling revealed distinct alterations associated with subsequent EOPE, from which GNA12circle was identified and validated as a candidate circulating marker. These findings support further investigation of circulating eccDNA for early EOPE risk assessment in larger multicenter populations.

Humans↗

PubMed2026

Neoplasms in prune belly syndrome: A novel case of early-onset metastatic bladder carcinoma and systematic review of reported tumors.

PURPOSE: Prune Belly Syndrome (PBS) is a rare congenital malformation complex characterized by cryptorchidism, urinary tract abnormalities and deficiency of the abdominal wall musculature. Although advances in neonatal and reconstructive care have substantially improved survival, the long-term risk of malignancy in this population remains poorly defined. We report a novel case of early-onset metastatic bladder carcinoma in a patient with PBS and perform a systematic review of all tumors described in association with the syndrome. METHODS: A systematic literature review was performed according to PRISMA guidelines and registered in PROSPERO (CRD420251072086). Databases searched through April 2025 included PubMed, Embase, Web of Science, ClinicalTrials.gov, Cochrane, and SciELO. Reported tumor cases in PBS patients were identified and classified as either PBS-associated or not. We additionally describe a new case of invasive bladder carcinoma. RESULTS: Seventeen studies comprising 20 patients met inclusion criteria. Tumors directly related to the genitourinary tract accounted for half of the cases. Bladder carcinoma was the most frequent neoplasm (35%), followed by hepatoblastoma (25%). Bladder tumors occurred at markedly younger ages and often presented as advanced diseases. Our index case involved a 33-year-old man with PBS who developed metastatic muscle-invasive urothelial carcinoma and died shortly after diagnosis. DISCUSSION: Improved survival in PBS has led to recognition of new late complications, including malignancy. Tumorigenesis may be influenced by chronic urinary stasis, infection, catheterization, cryptorchidism, and underlying genitourinary developmental abnormalities. These findings should be interpreted as hypothesis-generating given the limited number of reported cases. CONCLUSION: Although uncommon, malignancies in PBS may occur earlier and behave more aggressively than in the general population. Given the current level of evidence, careful long-term follow-up with clinical awareness is warranted, rather than routine invasive screening for all patients.

Humans↗

PubMed2026

Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D.

AIMS: Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS: Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS: SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS: Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.

Type 2 diabetes↗

PubMed2026

Genetic Screening of Colombian Patients With Early-Onset Parkinson Disease.

BACKGROUND AND OBJECTIVES: Early-onset Parkinson disease (EOPD), defined as symptom onset before 50 years of age, accounts for approximately 10% of patients and is suggested to have a greater genetic component than typical late-onset forms of the disease. Recessive variants in PRKN, PINK1, and DJ-1, are the most common genetic cause of EOPD, however, most studies are in patients of white ancestry. This study aims to analyze genetic variants in PRKN, PINK1, and DJ-1 in Colombian patients to help address the gap in EOPD genetic research of South American populations. METHODS: We analyzed 43 unrelated patients with EOPD using Sanger sequencing for the PRKN, PINK1, and DJ-1 genes and employed multiplex ligation-dependent probe amplification to detect copy number variants. Additionally, long-read whole-genome sequencing was conducted on 3 unresolved patients with age at onset before 30 years of age (long-read sequencing [LRS] patient A-C). RESULTS: We identified known pathogenic single-nucleotide variants and copy number variants in the PRKN gene accounting for 2 patients' disease (4.6% of patients). We observed 2 pathogenic variants in PRKN (c.155delA; p.N52Mfs*29 and c.1083+1G>A) in patient 1, who reported an age at onset of 16 years. We further detected a homozygous duplication of PRKN exons 5-6 in an additional patient, age at onset of 18 years. DISCUSSION: Our study helps characterize genetic contributors to EOPD in Colombian patients, demonstrating genetic forms (PRKN, PINK1, and DJ-1) are rare. Our results highlight a need to include diverse populations in research to improve genetic understanding of disease.

Journal Article↗

PubMed2026

Longitudinal comparison of treat-to-target states and clinical outcomes in patients with late-onset versus early-onset systemic lupus erythematosus.

OBJECTIVE: We compared demographic and clinical characteristics between patients with late-onset (LO) and early-onset (EO) systemic lupus erythematosus (SLE) and examined their longitudinal associations with treatment targets and long-term outcomes, irreversible organ damage accrual and health-related quality of life (HRQoL). METHODS: We analyzed prospectively collected data from patients enrolled in the Asia Pacific Lupus Collaboration cohort. Patients diagnosed with SLE at age >50 years were classified as LO-SLE and compared with those diagnosed at age ≤50 years (EO-SLE). Longitudinal associations with treatment targets (LLDAS and DORIS remission), organ damage accrual (SLICC/ACR Damage Index), and HRQoL (SF36v2 physical and mental component summary (PCS and MCS) scores) were examined using multivariable multilevel logistic, recurrent-event survival, and linear mixed-effects models, respectively. Disease activity, flares, medication exposure, and other clinical characteristics were also compared between groups. RESULTS: Among 3,917 patients studied, 346 (8.8%) had LO-SLE. Compared with EO-SLE, patients with LO-SLE had lower disease activity, lower glucocorticoid and immunosuppressant exposure, and higher attainment of treatment targets; LO-SLE was associated with higher odds of attaining LLDAS (OR: 2.33 (1.66, 3.28)) and DORIS remission (OR: 2.22 (1.45, 3.38)). However, they were at a greater risk of damage accrual (HR:1.82 (1.50, 2.21)) and lower PCS scores, meaning poorer physical health (regression coefficient (RC) = -3.63 (-4.58, -2.68)) but not MCS (RC= 0.68 (-.50, 1.86)). CONCLUSION: Despite higher attainment of treatment targets, patients with LO-SLE experienced greater damage accrual and poorer physical health, suggesting that disease activity targets alone may not fully capture outcome risk in LO-SLE.

Journal Article↗

PubMed2026

Polygenic risk score for early identification of coronary artery disease in a real-world clinical setting within the Latvian patient population.

STUDY OBJECTIVE: Polygenic risk scores (PRS) are increasingly recognized for their potential to improve coronary artery disease (CAD) prediction beyond traditional clinical models. This study evaluated the utility of genome-wide association study (GWAS) - derived PRS and pathway-specific PRS (PS-PRS) in the Latvian population, aiming to assess their association with CAD and compare their predictive performance with conventional risk factors. DESIGN PARTICIPANTS AND MAIN OUTCOME MEASURES: The study included 90 early-onset CAD patients and 43 controls with no evidence of atherosclerotic lesions on coronary angiography, with next-generation sequencing performed. PRS was calculated using 192 single nucleotide variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. The predictive accuracy of PRS, PS-PRS, clinical risk factors, and their combinations was analyzed via ROC curves. RESULTS: The average age was 48.7 years in CAD patients and 49.8 in controls. CAD patients showed significantly higher PRS (mean 0.31) compared to controls (mean - 0.65; p < 0.0001). PRS alone had moderate discriminatory power (AUC = 0.773), slightly lower than LDL cholesterol (AUC = 0.775) and total cholesterol (AUC = 0.821). Combining clinical risk factors improved prediction (AUC = 0.872), with the highest accuracy when PRS was integrated with all clinical factors (AUC = 0.933). The PRS distributions were significantly elevated in early-onset CAD patients across the angiogenesis/tissue repair pathway (p = 0.00038), inflammation pathway (p = 0.043), vascular remodelling pathway (p = 0.0116), and pathway of genes with unknown function in atherosclerosis (p = 0.0035), but overall PRS demonstrated superior discrimination compared to pathway-specific PRS. CONCLUSIONS: Incorporating PRS enhances early-onset CAD risk prediction. Pathway specific PRS had lower discriminative ability than the overall PRS.

Atherosclerosis↗

PubMed2026

A novel deep intronic EIF2AK3 variant disrupts splicing and causes Wolcott-Rallison syndrome.

AIM: Deep intronic variants can disrupt splicing and cause monogenic disease but are missed by routine genetic testing. This study assessed the contribution of deep intronic variants to Wolcott-Rallison syndrome (WRS), a recessive disorder characterized by early-onset diabetes and progressive multisystem disease caused by loss-of-function EIF2AK3 variants. METHODS: We investigated a cohort of 116 individuals referred to the Exeter Genomics Laboratory for genetic testing who had diabetes diagnosed at ≤2 years and at least one additional feature consistent with WRS: hepatic dysfunction, skeletal abnormalities or developmental delay. No genetic cause had been identified after testing all known early-onset diabetes genes. We screened genome-sequencing data for rare homozygous intronic EIF2AK3 variants. Candidate variants predicted to affect splicing by SpliceAI were assessed using a minigene exon-trapping assay. RESULTS: We identified two rare homozygous intronic EIF2AK3 variants in two siblings. Only one variant, c.1651-180G>T, was predicted to disrupt splicing in silico. The two children, born to consanguineous parents, were diagnosed with early-onset diabetes (diagnosed at 1 year and 21 weeks), hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. The minigene assay showed that c.1651-180G>T creates a cryptic donor splice site within intron 9, resulting in inclusion of a 79-nucleotide pseudoexon, causing a frameshift and premature stop codon. Using this evidence, the variant was reclassified as likely pathogenic according to ACMG/ACGS guidelines. CONCLUSIONS: We report the first deep intronic EIF2AK3 variant causing WRS, highlighting the need to consider systematic intronic analysis in unresolved cases.

EIF2AK3↗

PubMed2026

Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.

BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 potassium channel. While most pathogenic variants result in loss-of-function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. OBJECTIVES: To elucidate the genetic cause and functional LOF mechanisms underlying severe early-onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. METHODS: We evaluated twins presenting with early-onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole-exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. RESULTS: WES identified a heterozygous de novo p.L368P variant in the "TLGYG" selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant-negative effect on wild-type KV4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. CONCLUSIONS: Identifying the first pathogenic variant in the KV4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.

KCND3↗

PubMed2026

Differential contributions of mt-Tr and Cs variants to developmental cochlear defects and mitochondrial dysfunction in A/J mice.

A/J mice exhibit early-onset hearing loss linked to Cdh23, mitochondrial tRNA-Arg (mt-Tr), and citrate synthase (Cs) variants. Although developmental cochlear defects have been identified in juvenile A/J mice, the hierarchical contributions of mt-Tr versus Cs remain unclear. Using reciprocal intercross-derived strains to decouple mitochondrial haplotypes from nuclear factors, we demonstrate that the mitochondrial background is the primary determinant of auditory dysfunction. Mice with A/J mtDNA (AXB strains) displayed significantly higher ABR thresholds, accelerated hair cell attrition, and severe stereocilia dysmorphology compared to those with B6 mtDNA (BXA strains), occurring largely independently of the Cs genotype. While the Cs mutation exacerbated hearing loss, its impact was secondary to that of the dominant mitochondrial background. Systemic behavioral assessments and mitochondrial assays confirmed that A/J mitochondria exert a more profound metabolic impact than the Cs mutation. Our findings establish that the mitochondrial genomic background, with the mt-Tr locus as a prominent candidate variant, serves as the principal driver of developmental cochlear defects and early-onset hearing loss in A/J mice, while the nuclear Cs mutation acts as a synergistic modifier. This study underscores the critical role of mitonuclear crosstalk in inner ear maturation and provides new insights into the etiology of hereditary hearing loss.

Animals↗

PubMed2007

Multisystem Proteinopathy

CLINICAL CHARACTERISTICS: Multisystem proteinopathy (MSP) is a genetically heterogeneous, multisystem degenerative disorder characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset Paget disease of bone (PDB), and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease is 43 years, PDB is 41 years, and FTD is 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with MSP. DIAGNOSIS/TESTING: The diagnosis of MSP is established in a proband with typical clinical findings and a heterozygous pathogenic variant in VCP, HNRNPA1, HNRNPA2B1, or SQSTM1 identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Weight control to avoid obesity; physical therapy and stretching exercises to promote mobility and prevent contractures; occupational therapy and mechanical aids (canes, walkers, orthotics, wheelchairs) as needed for ambulation/mobility; surgical intervention for foot deformity and scoliosis as needed; respiratory aids when indicated; assisted living arrangements for muscle weakness and/or dementia; bisphosphonates to relieve pain and disability from PDB; social and emotional support; education regarding safety precautions. Surveillance: Echocardiogram and electrocardiogram with repeat cardiac evaluation every two to three years or earlier if symptomatic; annual pulmonary function studies; sleep studies as clinically indicated; annual alkaline phosphatase measurement; skeletal imaging as indicated for evaluation of PDB; neurologic and neuropsychological assessment every two to three years or more frequently as needed; multidisciplinary monitoring for respiratory, cardiac, musculoskeletal, and cognitive decline. GENETIC COUNSELING: MSP is inherited in an autosomal dominant manner. Most individuals diagnosed with MSP have an affected parent. Estimates based largely on VCP-MSP suggest that approximately 5% of individuals have a de novo pathogenic variant. Each child of an individual with MSP has a 50% chance of inheriting the MSP-related pathogenic variant. Marked intrafamilial variability may be observed among heterozygous family members, including differences in age at onset, severity, rate of progression, and the specific combination of manifestations. Once the MSP-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Inclusion Body Myopathy with Early-Onset Paget Dis↗

PubMed2026

Pathogenic Variants in HEPACAM Alter Protein Localization and Interactome in Astrocytes of the Developing Mouse Cortex.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, white matter edema, seizures, and motor and cognitive decline. Approximately 25% of MLC patients carry HEPACAM pathogenic variants, many of which are dominant missense variants causing remitting MLC Type 2b. HEPACAM encodes hepatic and glial cell adhesion molecule (hepaCAM), also known as GlialCAM, an astrocyte-enriched transmembrane protein with important roles in astrocyte territory establishment, gap junction coupling, branching organization, synaptic function, and development of the gliovascular unit. The molecular mechanisms through which pathogenic variants in HEPACAM alter hepaCAM protein function in vivo and facilitate MLC pathogenesis during brain development remain largely unknown. Here, we used new viral tools and proximity-based proteomics to examine how three different dominant pathogenic variants alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. We found dramatic changes in hepaCAM distribution throughout the astrocyte, which were common to all mutants tested. We also observed significant changes in protein interactome between wild type and mutant hepaCAM, including decreased association with previously described hepaCAM-interacting proteins Connexin 43 and CLC-2. Moreover, we identified the epilepsy-associate potassium channel KCNQ2 as a novel hepaCAM interaction partner and found reduced association between KCNQ2 and pathogenic variants. Collectively, our data provide new insights into hepaCAM protein function in astrocytes during brain development, reveal altered protein dynamics of pathogenic variants, and provide a new resource to explore the molecular underpinnings of MLC pathogenesis.

Animals↗

PubMed2026

Beyond Rett syndrome: a case series expanding the neurological spectrum associated with pathogenic MECP2 variants.

BACKGROUND: Although pathogenic variants in MECP2 are classically associated with Rett syndrome (RTT), increasing evidence suggests that they can underlie a broader spectrum of neurological phenotypes. Clinical manifestations may vary according to sex, variant type, residual protein function, and pattern of X-chromosome inactivation. METHODS: We describe five unrelated individuals carrying pathogenic MECP2 variants identified through multiplex ligation-dependent probe amplification, chromosomal microarray analysis, and next-generation sequencing. Clinical, neuroradiological, neurophysiological, and molecular findings were retrospectively reviewed. RESULTS: Two unrelated girls carrying large de novo Xq28 deletions encompassing the entire MECP2 locus presented with mild neurodevelopmental impairment and epilepsy, but no developmental regression or classic RTT features. Both girls showed borderline cognitive functioning and normal brain MRI. A 9-year-old boy carrying a maternally inherited MECP2 frameshift variant presented with intellectual disability, autism spectrum disorder, and focal epilepsy, whereas carriers in his family exhibited milder neuropsychiatric manifestations. A 44-year-old man carrying a MECP2 missense variant presented with an early-onset spastic-ataxic syndrome, peripheral neuropathy, and cerebellar dysfunction, while a 16-year-old girl patient carrying a distinct de novo MECP2 missense variant displayed isolated mild motor incoordination and subtle cerebellar signs with preserved cognitive functioning. CONCLUSIONS: Our findings expand the evidence that pathogenic MECP2 variants can produce neurological phenotypes distinct from classic RTT, including mild neurodevelopmental impairment without regression, and predominantly cerebellar or spastic-ataxic manifestations associated with limited cognitive involvement. Allelic heterogeneity seems to correlate with clinical phenotypes, at least in our small cohort. In conjunction with established diagnostic criteria, these observations support testing MECP2 in a selection of atypical neurodevelopmental and movement disorder presentations.

Humans↗

PubMed2026

Unraveling the Clinical Spectrum of DNASE1L3 Deficiency: Insights from Case Series and Systematic Literature Review.

BACKGROUND: DNASE1L3 deficiency is a rare monogenic cause of lupus and lupus-like autoimmunity resulting from impaired extracellular DNA clearance and sustained immune activation. Although most reported patients present with early-onset systemic lupus erythematosus (SLE), emerging evidence suggests broader phenotypic variability, including vasculitic and overlap manifestations. Whether these presentations represent distinct clinical entities or a continuum of DNASE1L3-associated immune dysregulation remains unclear. We aimed to define the clinical spectrum of DNASE1L3 deficiency and examine the relationship between recurrent pathogenic variants and disease severity. METHODS: We conducted a combined pediatric case series and systematic literature review. Four children with genetically confirmed biallelic DNASE1L3 variants followed at a tertiary pediatric rheumatology centre were retrospectively analysed for clinical, immunological, genetic, treatment, and outcome data. In parallel, a systematic search of PubMed/MEDLINE, Scopus, and Web of Science identified previously reported patients with confirmed biallelic pathogenic or likely pathogenic DNASE1L3 variants and extractable patient-level clinical data. To facilitate cross-case comparison, we applied an exploratory three-tier descriptive framework reflecting increasing disease severity: vasculitic or organ-limited disease (G1), systemic lupus or overlap phenotypes without irreversible organ damage (G2), and severe systemic organ-damaging disease (G3). The assigned grades were descriptive rather than permanent categories, as some patients may meet the criteria for a higher grade if broader systemic manifestations or irreversible organ damage develop during follow-up. FINDINGS: Fifteen reports provided extractable patient-level data, corresponding to 45 unique previously reported patients after accounting for known or probable overlapping reports. Combined with four patients from our centre, the analysis included 49 genetically confirmed individuals. SLE-dominant disease was the most frequent phenotype (27 [60%] of 45), followed by hypocomplementaemic urticarial vasculitis/HUVS-dominant disease (10 [22.2%]) and overlap phenotypes (8 [17.8%]). Renal involvement was reported in 30 (66.7%) of 45 patients, and disease onset occurred by age 3 years in 20 (44.4%). Persistent hypocomplementemia affecting C3 and C4 was frequently reported across the spectrum. Recurrent DNASE1L3 variants were observed across multiple phenotypic and severity grades. Variants such as p.Asn191Ser and p.Thr97Ilefs*2 occurred in patients spanning organ-limited vasculitic disease, lupus overlap phenotypes, and severe multisystem lupus with major organ involvement. CONCLUSION: DNASE1L3 deficiency was associated with a broad clinical spectrum of immune-mediated disease rather than a single clinicopathological entity. The occurrence of identical pathogenic variants across distinct phenotypic and severity states argues against a simple genotype-phenotype model and suggests that additional modifiers influence disease expression.

Humans↗

PubMed2026

Real-world clinical utility of exome sequencing in pediatric drug-resistant epilepsy: Experience from a tertiary center in Thailand.

BACKGROUND: Genomic testing has increasingly contributed to the diagnosis and management of pediatric drug-resistant epilepsy (DRE), particularly in patients with suspected genetic etiologies. This study evaluated the diagnostic yield and real- world clinical utility of whole-exome sequencing (WES) in children with DRE. METHODS: Children with DRE and seizure onset before 15 years of age were enrolled between January 2020 and December 2023. Clinical data, including demographics, seizure characteristics, developmental history, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and prior investigations, were reviewed. WES was performed in all probands and, when available, their parents. Variants were interpreted according to standard guidelines. Clinical utility and 1-year seizure and developmental outcomes were assessed from follow-up records. RESULTS: Fifty-six patients (23 males, 33 females) were included. The median age at seizure onset was 1 year (interquartile range [IQR] 0.3-4 years), and 96.4% had developmental comorbidities. Pathogenic or likely pathogenic variants were identified in 39% (22/56), with the highest diagnostic yield in children with seizure onset before 3 years of age. Channelopathies accounted for most genetically solved cases (68%), predominantly involving sodium channel genes. Genetic diagnoses provided clinical utility in 73% (16/22) of solved cases by guiding treatment and precision management. At 1-year follow-up, genetically solved patients showed more favorable seizure and developmental outcomes than those with genetically unsolved patients. CONCLUSION: WES achieved a 39% diagnostic yield and substantial clinical utility in pediatric DRE, particularly in early-onset and channelopathy-related disorders. These findings support early molecular diagnosis to facilitate genotype-informed management in appropriately selected children. However, the more favorable developmental and seizure outcomes observed in genetically solved patients should be interpreted with caution, as they may have been influenced by multiple factors beyond genetic diagnosis. In resource-limited settings, careful clinical phenotyping remains essential for treatment decisions and for prioritizing children for genomic testing.

Clinical utility↗

PubMed2026

Regional and statewide hysterectomy-corrected endometrial cancer incidence and five-year relative survival in Texas.

BACKGROUND: Rising endometrial cancer (EC) incidence nationwide, particularly among Hispanic women, and high prevalence of risk factors such as obesity and comorbidities in Texas, motivated us to estimate EC incidence rates (IRs) and survival by age (<50 years/ early-onset, ≥50 years/late-onset), race-ethnicity (Non-Hispanic-White [NHW], -Black [NHB], Hispanic), histology (endometrioid, non-endometrioid), and area-based socioeconomic (SES) factors across Texas Health Service Regions (HSRs). STUDY DESIGN: Between 2000 and 2019, a total of 42,571 women (20-79 years) with EC were reported from Texas within the Surveillance, Epidemiology, and End Results Program. IRs and 5-year relative survival were calculated using SEER*Stat. IRs were corrected for hysterectomy using Behavioral Risk Factor Surveillance System data. RESULTS: Statewide EC IRs rose from 38.5 (2000-2009) to 44.5 (2010-2019), with the highest increase in the Upper-South (42.6 to 53.8). Across HSRs, Upper-South consistently had higher IRs among women < 50 (13.9) and ≥ 50 years (112.7). Among those < 50 years, Hispanics had the highest IRs (12.4), predominantly endometrioid tumors, whereas in women ≥ 50 years, NHB had the highest IRs (119.2) with a large proportion of non-endometrioid tumors. IRs were higher in areas with lower poverty, and higher education, income, and urbanization. Associations with unemployment were mixed. Worse survival outcomes were observed among NHBs, non-endometrioid, advanced-stage, and lower SES. Central Texas had more favorable survival outcomes compared to other HSR. CONCLUSION: EC IRs and survival rates in Texas largely mirror national trends, with regional differences likely reflecting sociodemographic and histologic distributions.

Humans↗

PubMed2026

Incidence of Atrial and Ventricular Arrhythmias in Patients With Titin Truncating Variants Across the Ventricular Morphofunctional Phenotypic Spectrum.

BACKGROUND: Titin truncating variants (TTNtvs), the most common genetic cause of dilated cardiomyopathy (DCM), are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD), suggesting they can cause arrhythmias before development of overt ventricular cardiomyopathy. OBJECTIVES: This study sought to compare the incidence of atrial and ventricular arrhythmias (VAs) between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, nondilated left ventricular cardiomyopathy (NDLVC), and DCM. METHODS: A retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with pathogenic/likely pathogenic TTNtvs. Patients were classified as having G+/P- disease, NDLVC, or DCM using the 2023 European Society of Cardiology guideline for cardiomyopathies. The incidence of AF, sustained VA, appropriate defibrillator therapies, SCA, and SCD was ascertained from medical records. RESULTS: Among 253 TTNtv-positive patients (mean age of 45 ± 16 years; 59% male), 54 (21%) were G+/P-, 49 (20%) were NDLVC, and 150 (59%) were DCM. During a median follow-up of 3.8 years at our institution, new-onset AF was seen in 67 patients (26% of those at risk). There was no significant difference in survival from new-onset AF in patients with NDLVC (HR: 3.29; 95% CI: 0.71-15.3; P = 0.13), although DCM was associated with worse AF-free survival (HR: 4.86; 95% CI: 1.17-20.1; P = 0.03). New-onset VAs were seen in 44 (17%) patients during follow-up, including SCA in 12 (5%) patients. There was no association between NDLVC (HR: 0.71; 95% CI: 0.19-2.69; P = 0.62) and DCM (HR: 0.97; 95% CI: 0.37-2.54; P = 0.95) phenotypes compared with G+/P- patients. Cardiac transplantation was done in 14 (6%) patients, and 6 (2%) died of cardiac causes, including 2 cases of SCD. CONCLUSIONS: When stratified by morphofunctional phenotype, there was no difference in VAs across morphofunctional phenotypes in patients with TTNtvs. This highlights that patients with TTNtvs may be at risk of SCA/SCD even without overt ventricular cardiomyopathy. The risk of new-onset AF was highest in patients with DCM but was seen at all phenotypic stages during follow-up.

arrhythmia↗

PubMed2026

Mechanisms linking the gut microbiota to colorectal cancer development and progression.

Colorectal cancer remains a leading cause of global cancer mortality, with a concerning rise in early-onset cases driven by complex interactions between environmental exposures, lifestyle factors, and host genetics. Mounting evidence indicates that gut microbiota dysbiosis critically modulates this oncogenic process, acting as an active participant rather than a passive bystander. This review systematically synthesizes the dichotomous roles of the intestinal microbiome in colorectal tumorigenesis through the conceptual framework of the driver-passenger model. We discuss how early initiating driver bacteria, such as Polyketide synthase-positive Escherichia coli and enterotoxigenic Bacteroides fragilis, compromise mucosal barriers, induce chronic mucosal inflammation, and inflict direct genomic instability. As the local tumor microenvironment undergoes profound metabolic remodeling, opportunistic passenger pathogens, notably Fusobacterium nucleatum, become enriched, further promoting cellular proliferation and facilitating tumor immune evasion. Conversely, protective commensals, exemplified by Clostridium butyricum and Streptococcus thermophilus, exert robust tumor-suppressive effects through multifaceted mechanisms. These beneficial microbes actively antagonize malignant progression by redirecting tumor metabolic fluxes toward oxidative stress, orchestrating deep epigenetic reprogramming, and degrading core oncoproteins to reverse chemoresistance. Transitioning from fundamental mechanisms to clinical application, we evaluate a comprehensive spectrum of microbiota-targeted interventions, encompassing non-invasive diagnostic biomarkers, fecal microbiota transplantation, engineered bacteria, phage therapy, and postbiotics. Finally, we critically address the formidable translational challenges associated with microbial heterogeneity, long-term safety, and regulatory standardization, aiming to provide a balanced perspective on integrating microbiome-based strategies into next-generation precision oncology for colorectal cancer.

Humans↗

PubMed2026

Paediatric outcomes after maternal nipocalimab for haemolytic disease of the fetus and newborn: an open-label, single-arm study.

OBJECTIVES: To describe haemolytic disease outcomes, growth, neurodevelopment and health-related quality of life (HRQoL) through 24 months of life in infants exposed to nipocalimab in pregnancies at high risk of early-onset severe haemolytic disease of the fetus and newborn (EOS-HDFN). DESIGN: A multicentre, open-label, single-arm trial. SETTING: Centres with expertise in HDFN management. PATIENTS: Pregnant individuals with previous EOS-HDFN and maternal anti-D titres ≥32 or anti-K titres ≥4. INTERVENTIONS: Weekly nipocalimab (30 and/or 45 mg/kg) from 14 to 35 gestational weeks. MAIN OUTCOME MEASURES: Infants' cord-blood alloantibody titres at birth, HDFN management, growth through 6 months, neurodevelopment (caregiver-reported Ages and Stages Questionnaire, third edition (ASQ-3)) and HRQoL assessments through 24 months of life. RESULTS: Of 13 pregnancies, 12 resulted in live births; one fetal loss occurred due to intrauterine transfusion (IUT) complications. A single simple transfusion was administered in one of seven infants delivered after a maternal nipocalimab course without IUTs, where cord blood alloantibody titres were <8. Multiple transfusions (one to seven simple transfusions/infant; one exchange transfusion) were administered to five infants delivered after early nipocalimab discontinuation and IUTs, with cord-blood alloantibody titres ranging from 512 to 32 768. No unusual growth patterns were observed through 6 months. No neurodevelopmental delays were identified through 24 months of life, with mean ASQ-3 domain scores within normal ranges. HRQoL outcomes were positive across physical, emotional, social and cognitive functioning. CONCLUSIONS: Maternal nipocalimab in pregnancies at high risk of EOS-HDFN may reduce adverse neonatal outcomes correlating with low cord-blood alloantibody titres, without affecting growth through 6 months, neurodevelopment or HRQoL through 24 months of life. TRIAL REGISTRATION NUMBER: NCT03842189.

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