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PubMed2025

Ten years of exome sequencing and reanalysis among racial, ethnic, and ancestral groups: The importance of equitable reanalysis access.

PURPOSE: Race, ethnicity, and ancestry (REA) affect the diagnostic utility of genetic testing. In addition to barriers to accessing genetics services, some non-European REA groups experience decreased diagnostic results and increased uncertain results. Exome sequencing (ES) is a unique genetic test because data can be reanalyzed with new information and variants may be reclassified after the original result. METHODS: We performed a retrospective review of 10,416 clinical ES cases originally analyzed by Ambry Genetics between 2011 and 2021 with reanalysis events through 2023. The relationship between assigned REA group, ES result, reanalysis and reclassification rates, and reanalysis initiators were analyzed with logistic regression. RESULTS: Reanalyses increased the total diagnostic yield from 21.4% to 25.5%. There were no significant differences in reclassification rate among REA groups. However, the African American and Black group (P = 2.8E-07), the Hispanic and Latino group (P = .0022), and the Asian group (P = .033) were significantly less likely to receive provider-initiated reanalysis compared with the White group. CONCLUSION: Although reclassification rates were not found to be associated with REA group, not all REA groups had the same access to ES reanalysis. Laboratory-initiated proactive reanalysis can help reduce disparities in ES diagnostic utility by reducing barriers to accessing reanalysis.

Female↗

PubMed2025

Impact of laboratory-driven proactive reanalysis: Reclassification to positive in 5% of initially negative or uncertain exome sequencing cases.

PURPOSE: Reanalysis of exome sequencing (ES) data increases diagnostic utility; however, there is no consensus on when and under what circumstances reanalysis should occur. Requesting and performing ES reanalysis burdens both clinical and laboratory workflows. Maximizing the potential for reclassification is essential. Here, we describe the impact of a laboratory-driven proactive reanalysis process that triggers reanalysis when new evidence is identified. METHODS: We reviewed reanalysis outcomes of an ES cohort. Reanalysis events were categorized based on initiating factors (laboratory-driven proactive, family studies, and clinician-initiated). Laboratory-driven proactive reclassifications are prompted by systematic review of new scientific data. Outcomes were evaluated by initiating factors, reclassification types, evidence used, and time since original report. RESULTS: Overall, 23% of cases underwent at least 1 reanalysis, with 35% of reanalyses resulting in reclassification. There was a 4% increase in diagnostic yield, including 5% of initially unsolved ES receiving diagnostic reports. Diagnostic reclassifications rates were significantly higher for laboratory-driven proactive reanalyses (54%; P < .0001) than family studies (18%) and clinician-initiated reanalyses (4%). New gene-disease relationships were the most efficacious evidence source. Laboratory-driven proactive reclassifications occurred steadily over time. CONCLUSION: Laboratory-driven proactive reanalysis effectively provides more diagnostic reclassifications compared with clinician-initiated reanalysis. Laboratories should curate and integrate emerging evidence into ES reanalysis.

Humans↗

PubMed2025

Diagnostic Yield After Postnatal Reanalysis of Prenatal Exome Sequencing Results.

OBJECTIVE: Analysis of exome sequencing (ES) relies on correlation with phenotypic features, but fetal phenotyping is often incomplete. The additional yield of postnatal follow-up in cases with negative or inconclusive prenatal ES has not been demonstrated. Our objective was to assess the incremental diagnostic yield of ES reanalysis after initially negative prenatal ES for congenital anomalies incorporating features identified postnatally. METHODS: This was a secondary analysis of two prospective cohort studies of ES for fetal anomalies. We included cases in which initial ES utilizing the prenatal phenotype was not diagnostic. The primary outcome was incremental diagnostic yield of ES when incorporating postnatal findings. RESULTS: Eighty-seven cases with negative or inconclusive prenatal ES and postnatal follow-up available were included. Of those, 56 (64%) had new findings postnatally. There was an incremental yield of 2% in the entire cohort, and 7% in those with new postnatal findings. In two additional cases, postnatal evaluation suggested a specific genetic diagnosis that was not detectable with ES. CONCLUSION: Among pregnancies with fetal anomalies and no clear diagnosis identified by prenatal ES, postnatal follow-up is recommended. Reanalysis of ES results can result in a genetic diagnosis in 7% of cases with new findings.

Humans↗

PubMed2026

Comparative effectiveness of torsemide vs furosemide in the management of heart failure patients: Win-ratio reanalysis of the TRANSFORM-HF trial.

BACKGROUND: Loop diuretics are widely used for managing congestion in patients with heart failure (HF). The TRANSFORM-HF trial is a multicenter randomized study that enrolled heart failure patients, comparing a strategy of torsemide vs furosemide. The time-to-event analysis demonstrated neutral effects on all-cause death at 30 months and the composite of all-cause death and first rehospitalization at 12 months. We evaluated whether a hierarchical win-ratio (WR) framework integrating mortality, recurrent hospitalization, and patient-reported health status provides additional interpretive insight. METHODS: This study is a secondary analysis of the pragmatic, multicenter, open-label, randomized TRANSFORM-HF trial, conducted across 60 US hospitals that randomized 2,859 patients hospitalized with HF to torsemide or furosemide. The primary 12-month hierarchical composite outcome was defined as (1) all-cause mortality, (2) recurrent all-cause hospitalizations, and (3) lack of improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). The primary statistical method was a WR analysis adjusting covariates via inverse probability weighting. Subgroup analyses evaluated potential heterogeneity across patient demographics and clinical characteristics. RESULTS: In the primary 12-month intention-to-treat analysis, the adjusted WR was 1.07 (95% CI, 0.98-1.16; P = .13), indicating no significant difference between torsemide and furosemide. A supplementary 30-month analysis with extended mortality follow-up yielded a similar estimate (adjusted WR, 1.06; 95% CI, 0.98-1.16; P = .14); hospitalization and KCCQ-CSS components were assessed through 12 months. As-treated sensitivity analyses were consistent with the neutral primary findings. Exploratory subgroup analyses were not adjusted for multiplicity and should be considered hypothesis-generating. CONCLUSIONS: The overall WR comparison between torsemide and furosemide showed no statistically significant difference in the primary 12-month analysis. The WR framework provided an interpretive decomposition across outcome domains but did not establish superiority of either loop diuretic strategy. All findings should be considered exploratory. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03296813, https://clinicaltrials.gov/study/NCT03296813.

Aged↗

PubMed2025

Identification of maternal Gγ(Aγδβ)0 thalassemia through retrospective reanalysis of prenatal cfDNA sequencing data.

OBJECTIVE: Non-invasive prenatal screening (NIPS) is widely used to detect chromosomal abnormalities such as trisomies 21, 13, and 18 and is also effective in screening for copy number variations (CNVs). However, the routine application of NIPS to detect smaller CNVs within the HBB gene, specifically Gγ(Aγδβ)0 thalassemia, has yet to be well documented. This study aims to evaluate the efficacy of cfDNA-based maternal carrier screening in routine screening for Gγ(Aγδβ)0 thalassemia. METHODS: We performed a retrospective analysis of 107,300 pregnant women who underwent NIPS at Longgang Maternal and Child Healthcare Hospital in Shenzhen from December 2017 to May 2022. Using an improved algorithm, we reanalyzed NIPS data to identify maternal Gγ(Aγδβ)0 thalassemia. Positive cases were confirmed by multiplex ligation-dependent probe amplification (MLPA) using peripheral blood leukocytes. RESULTS: Among the 107,300 NIPS analyses, 38 maternal deletion CNVs within the HBB gene were identified using the improved algorithm, with a prevalence of 0.035% (38/107,300). MLPA confirmed that all detected deletions were consistent with Gγ(Aγδβ)0 thalassemia. The positive predictive value (PPV) for detecting Gγ(Aγδβ)0 thalassemia by cfDNA-based maternal carrier screening was 100%. Among the 38 Gγ(Aγδβ)0 cases, 9 were also associated with α-thalassemia deletions, including 4 cases with -SEA/αα, 4 with -α3.7/αα, and 1 with -α4.2/αα. No cases of homozygosity or compound HBB gene variants were observed. CONCLUSIONS: Gγ(Aγδβ)0 thalassemia is not uncommon in China, and repurposed NIPS methodology for maternal genomic analysis in detecting HBB gene deletions is a reliable method for identifying maternal carriers of this disease.

Humans↗

PubMed2026

A reanalysis of the Hitachi cohort study evaluating the effectiveness of low-dose CT screening for lung cancer.

The effectiveness of low-dose thoracic computed tomography (CT) screening for lung cancer for non-smokers or light smokers has been unclear. The results of the Hitachi cohort study performed by the conventional multivariable analysis suggested the reduction of lung cancer mortality by thoracic CT screening, but also revealed the lower all-cause mortality in the CT group, which indicated the existence of self-selection bias. Because the background of the subjects in the CT screening group and that in the X-ray screening group were very different, it is critical to adjust appropriately the confounding factors. In this brief report, we describe a re-evaluation of the results of the Hitachi Cohort Study performed by using more flexible methods, propensity score matching and inverse probability weighting.

epidemiology/public health↗

PubMed2026

Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.

BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

Humans↗

PubMed2017

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability.

While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

Adult↗

PubMed2026

Genus-Wide Pan-Genome Analysis of Populus bZIP Transcription Factors with Reanalysis of Public Salt-Stress Transcriptomes.

Basic leucine zipper (bZIP) transcription factors regulate plant development and stress responses, but their genus-wide diversity in Populus remains unclear. We analyzed 19 Populus genomes and retained 1764 bZIP proteins, including 21 independent new loci and four annotation corrections. Of these, 1762 were assigned to 79 orthologous gene groups (OGGs), comprising 43 core, 20 soft-core, 15 shell and one cloud OGG, of which 59 showed copy-number variation. Phylogenetic analysis assigned 74 representative pangenes to 13 subfamilies, with five remaining unclassified and motif patterns differing among subfamilies. Whole-genome duplication (WGD)/segmental duplication accounted for 81.0% of OGG-assigned proteins and contributed predominantly to the conserved component. Although 72.2% of bZIP proteins overlapped a transposable element within the gene body or 2-kb flanks, this proportion was modestly lower than in matched non-bZIP genes, and copy-number-variable OGGs showed no greater TE coverage than invariant OGGs. Among retained homologous comparisons, 97.6% had Ka/Ks ≤ 1, supporting predominant purifying selection. Across the heterogeneous public salt-stress RNA-seq datasets analyzed, no OGG showed a significant, directionally concordant response in at least two Populus taxa. These results reveal a conserved bZIP framework shaped mainly by ancient duplication alongside variable genomic contexts and transcriptional responses.

Populus↗

PubMed2025

Long-term follow-up of children who received rapid genomic sequencing.

PURPOSE: To explore long-term trajectories of children who received rapid genome sequencing (RGS) in intensive care settings. METHODS: We examined the electronic health records of 67 critically ill pediatric patients who received RGS 6 to 8 years ago with a collective initial diagnostic yield of 46%. RESULTS: The median length of follow-up was 6.2 years (interquartile range 4.0-7.2 years). RGS-diagnosed patients had a longer average follow-up time compared with undiagnosed patients (5.9 years vs 4.8 years, P = .026) and more subspecialty appointments per follow-up year (9.4 vs 6.9, P = .036). Mortality during the follow-up period was 9%. Patients averaged 2.1 hospital readmissions per follow-up year and 28.1 hospitalized days per follow-up year. Forty-four patients (66%) had a documented new phenotype in the electronic health records during their follow-up period. Seven patients received clinician-driven reanalysis during the follow-up period, yielding 1 new diagnosis. Systematic reanalysis of RGS performed as part of this study identified 4 new candidate diagnoses. CONCLUSION: Pediatric patients who receive RGS during intensive care unit hospitalizations continue to be high health care utilizers in subsequent years, regardless of whether RGS identified a diagnosis. Additionally, two-thirds of this cohort had a documented phenotypic change over the follow-up period, indicating dynamic clinical evolution in the years after RGS.

Humans↗

PubMed2026

An economic evaluation of functional genomic testing for individuals with undiagnosed rare disorders.

PURPOSE: Functional genomics (FG) approaches, such as RNA-seq and proteomics, offer a complementary diagnostic modality for individuals whose cases remain unsolved after genomic sequencing. This study evaluates the cost-effectiveness and cost-benefit of FG for individuals with suspected monogenic disorders relative to manual reanalysis of genomic data at 18 months. METHODS: A decision tree model compared the costs and outcomes of FG and 18-month reanalysis using data from two Australian Undiagnosed Disease Programs. Deterministic and probability sensitivity analysis were performed. RESULTS: With a diagnostic yield of 13%, FG enabled 4 additional diagnoses per 100 individuals tested at an additional cost of $390 (US $240), resulting in an incremental cost-effectiveness ratio of $8,550 ($5,313) and an 85% probability of being cost-effective. CONCLUSION: Functional genomics enables timely diagnosis for individuals with suspected monogenic disorders by evaluating the functional impact of variants of uncertain significance, offering an advantage over reanalyzing genomic data at 18 months. Integration into the Australian healthcare system, supported by collaborative networks and secure data-sharing infrastructure, coupled with addressing barriers to accessing funded genomic testing, could lead to an annual net benefit of up to $1.1 million ($0.7 M).

Functional genomics↗

PubMed2026

Germline ATM Testing in Hereditary Cancer Syndromes: Feedback from a Five-Year Center Cohort.

PURPOSE: Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer. METHODS: We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible. RESULTS: Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10-9) for pancreatic cancer. CONCLUSION: This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.

ATM↗

PubMed2026

Network-based integration of metabolomics data from large-scale repositories.

INTRODUCTION: Public metabolomics data repositories such as MetaboLights and Metabolomics Workbench host rapidly growing volumes of raw data, processed results, and metadata. As data deposition becomes a prerequisite for funding and publication, there is an increasing need for tools that enable integration and joint reanalysis of datasets across studies to maximise reuse and reproducibility. OBJECTIVES: This study aims to enable large-scale integrative meta-analysis of public metabolomics data, exploiting harmonised metabolite annotations to identify robust multi-study metabolite and pathway signatures and to provide global visual overviews of repository content. METHODS: We developed a network-based integration framework operating at both the study (dataset) level and the metabolite or pathway level. Metabolite-level meta-networks integrate studies with shared biological context using co-occurrences of differential metabolites represented as bipartite graphs. Study-level networks compare observed metabolites for overall repository exploration. Networks can be explored interactively using a dedicated Python Dash app available at https://github.com/EloisaRL/Metabolomic-data-analysis-app/tree/main . RESULTS: As an example, the approach was applied to six COVID-19 plasma datasets from MetaboLights generated using LC-MS and NMR. Ten metabolites were identified as differential in at least three studies, including consistently up-regulated pyroglutamic acid, in agreement with the literature. Pathway-level networks provided an overview of shared biological processes across studies. A global network of 1,181 studies in Metabolomics Workbench demonstrated clustering by assay coverage and associated metadata, as expected. CONCLUSION: Network-based integration of harmonised metabolomics data enables robust cross-study analyses and highlights the critical importance of standardised annotation pipelines. Such approaches enhance the reuse, reproducibility, and impact of public metabolomics datasets, accelerating biological discovery.

Metabolomics↗

PubMed2026

Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.

The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous ρ-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as ρ moves Q6→H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at α=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p≤10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.

Codon reassignment↗

PubMed2026

Discordant neoplasms in monozygotic twins with a germline RECQL5 variant.

RECQL5 is a member of the RecQ helicase family involved in DNA replication, homologous recombination, and maintenance of genomic stability. While germline pathogenic variants in other RecQ helicases cause established cancer predisposition syndromes, the role of RECQL5 in human cancer susceptibility remains uncertain. We report monozygotic adolescent twins with distinct tumors: dysembryoplastic neuroepithelial tumor in one twin and Burkitt lymphoma in the other. Clinical genome sequencing was initially nondiagnostic, but reanalysis identified a rare heterozygous nonsense variant in RECQL5 (NM_004259.7:c.2698C>T, p.(Gln900Ter)), present in both twins and their unaffected mother. The variant is predicted to undergo nonsense-mediated mRNA decay or produce a truncated protein lacking the C-terminal SRI (Set2-Rpb1 interacting) domain, which mediates interaction with RNA polymerase II. However, tumor sequencing data were not available to evaluate loss of heterozygosity or second somatic events. Given the unaffected carrier parent, lack of tumor molecular confirmation, and the biological heterogeneity of the tumors, a causal relationship for this variant cannot be established. This case highlights the challenges of interpreting rare germline variants in genes with emerging but incompletely characterized disease associations. Although the available evidence is insufficient to establish a definitive causal relationship, the identification of a shared loss-of-function RECQL5 variant in monozygotic twins with distinct tumors is noteworthy and adds to the limited clinical evidence suggesting a potential role for RECQL5 in cancer susceptibility. Additional functional studies, tumor-based analyses and the accumulation of well-characterized clinical cases will be essential to determine whether RECQL5 contributes to hereditary cancer predisposition.

Adolescent↗

PubMed2026

Metadomain and metaloop genome interactions in mammalian T cells.

Recent studies have advanced understanding of chromosomal organization and its role in gene regulation, yet most analyses focus on short-range interactions (<2 Mb), limiting insight into broader architecture. The relationships between topologically associating domains (TADs), sub-TAD loops, cross-TAD interactions, and chromosomal compartmentalization remain poorly understood. Here, using high-resolution Hi-C analysis, we identify extensive multi-megabase and interchromosomal interactions (metaloops) in T lymphocytes that organize into meta-TAD associations (metadomains). These metaloops connect distal promoters and regulatory elements of genes functionally important in T cells, including Ctla4, Ikzf2, Il2ra, Ets1, and Foxo1. Reanalysis of mouse and human datasets confirms their reproducibility and dependence on superenhancers. Genome-wide clustering reveals three distinct interchromosomal hubs, including a superenhancer-enriched hub linked to T cell-specific gene activation. Integrative analysis of regulatory genomics data identifies factors associated with short- versus long-range interactions. This study introduces a broadly applicable computational framework and reveals features of T cell genome organization.

Animals↗

PubMed2026

Tn125-borne blaNDM-1 is decoupled from clonal background in a transcontinental Acinetobacter baumannii ST126/KL14 lineage.

BACKGROUND/OBJECTIVES: Carbapenem-resistant A. baumannii (CRAB) is a WHO Critical Priority pathogen. The blaNDM-1-carrying ST126/KL14 lineage has been independently reported from Vietnam (2015), Malaysia (2016), the USA (2023-2026), and Costa Rica (2024). Whether these geographically distinct reports represent a single transcontinental clone and through what mechanism blaNDM-1 disseminates has not been formally tested. METHODS: We performed comprehensive whole-genome reanalysis of the Vietnamese sentinel isolate DMS06669_L1 using three nested panels (n = 19, n = 138, and n = 609 Vietnamese A. baumannii genomes) and surveyed 429 plasmids extracted from 99 NDM-1 A. baumannii genomes retrieved from NCBI Pathogen Detection. RESULTS: Four ST126/KL14 isolates share high inter-regional average nucleotide identity (ANI; 99.77-99.92%) but wide intra-clade core-SNP distances (41-731 SNPs, well above the ∼20-40-SNP range typical of single-outbreak transmission clusters) and lack a significant molecular clock, consistent with a related transcontinental lineage rather than a single recent clone. NDM-1 plasmid evolution is statistically uncorrelated with chromosomal sequence type (Spearman ρ = 0.131, P = 0.573). At 609-strain population scale, under a fragmentation-aware detection criterion, all 41 blaNDM-1-carrying Vietnamese strains also carry ISAba125, with none carrying blaNDM-1 without it (Fisher exact test; Haldane-Anscombe-corrected OR ≈2.0 × 10³, 95% CI 1.2 × 10² to 3.4 × 10⁴; P = 4.74×10⁻⁴⁸; φ = 0.79). CONCLUSIONS: The blaNDM-1 dissemination pattern in this ST126/KL14 lineage is primarily consistent with Tn125 transposition acting alongside plasmid-borne spread. Standard MLST-based surveillance is insufficient; multi-level genomic monitoring - including chromosomal and plasmid-level detection of the Tn125/ISAba125 unit - is required to track this resistance threat.

A. baumannii↗

PubMed2024

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

PURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.

Humans↗