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PubMed2024

Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data.

UNLABELLED: Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time. SIGNIFICANCE: We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.

Humans↗

PubMed2026

Artificial intelligence-assisted clinical exome sequencing: Insights and outcomes from 822 pediatric diagnoses.

PURPOSE: This retrospective study examined the clinical and genetic characteristics of pediatric patients undergoing clinical exome sequencing (ES) and evaluated the performance of a commercially available artificial intelligence (AI) platform that was integrated into our analysis pipeline. METHODS: ES was performed in 822 consecutive patients at a single clinical laboratory. AI-based tools were used to jointly assess genetic information and the proband's Human Phenotype Ontology terms to support variant prioritization during the initial case review. RESULTS: A definitive molecular diagnosis was established in 22% (181 of 822) of index cases, while 40% (325 of 822) had variants of uncertain significance. Among those with a definitive diagnosis, 93% (168 of 181) had a single finding and 7% (13 of 181) had multiple findings. Of the 152 reported pathogenic/likely pathogenic variants in the fully resolved cases, 98.7% were successfully flagged by AI, and 75.0% ranked among the top 10 "most likely" variants. CONCLUSION: Clinical ES provides a substantial diagnostic yield in complex pediatric disorders. Integration of AI-powered platforms can accelerate phenotype-driven variant prioritization and facilitate rare disease diagnostics, but underscores the need for careful validation and optimization in clinical workflows.

Artificial intelligence↗

PubMed2026

Assessing the readiness of Oxford Nanopore sequencing for clinical genomics applications.

Long-read sequencing (LRS) technologies, namely, Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio), have emerged as promising solutions to overcome the limitations of short-read sequencing (SRS). Nevertheless, the still higher sequencing error rates compared with SRS, need for customized pipelines, rapidly updating software, and incipient scalability continue to present challenges for adopting ONT in standard clinical practice. Here we assess the performance of ONT (R9 and R10 chemistries) in comparison to Illumina and MGI across 17 well-characterized reference samples with 11 clinical variants representing nine different genetic diseases. To enable this, we have implemented a production-ready pipeline including SNV, indel, STR, SV, and CNV detection, alongside reporting key summary metrics to ensure high-quality data at the production sequencing level. Our results show high accuracy of ONT across SNVs (F-score 0.978-0.983) and SVs (F-score = 0.75) but still weaknesses across indels (F-score 0.659-0.758). However, we highlight that ONT accurately detected all four pathogenic indels as well as the performance improvement in exons and with the newer R10 chemistry. We further demonstrated the importance of long reads to detect clinically impactful variants such as a FMR1 pathogenic expansion, often misclassified by SRS as being in the premutation range. Our multiplatform analysis and Sanger validation uncovered a 1 bp error in the Coriell annotation for a cystic fibrosis-causing indel in GM07829. This work underscores the growing readiness of ONT for clinical applications, highlighting both its advancements and its potential for broader adoption in clinical genomics and large-scale operations.

Humans↗

PubMed2026

Library strategies differentially shape microbial, functional, and host signals in clinical metagenomic sequencing.

Metagenomic next-generation sequencing (mNGS) is increasingly used in infectious disease diagnostics, yet how library preparation shapes the microbial, functional, and host signals recovered from clinical samples remains poorly defined. Here, we performed a within-sample parallel comparison of three mNGS library preparation strategies-DNA-based libraries (DNAlib), RNA-based libraries (RNAlib), and total nucleic acid-based libraries (TNAlib)-across a diverse range of clinical specimens spanning five sample types. Using a curated clinical infectome as a benchmark, we show that library strategies are not interchangeable but capture distinct biological dimensions of the same specimen. RNAlib provided the most comprehensive standalone recovery of the clinical infectome, with improved detection of RNA viruses and cellular pathogens, enhanced resolution of resistance and virulence signals, and preservation of infection-associated host immune signatures. DNAlib showed stronger baseline recovery of DNA viruses and broader host genome coverage, whereas the TNAlib workflow evaluated here largely behaved as an intermediate strategy rather than a consistent improvement over dedicated DNA- or RNA-based workflows. Together, these results establish that the library preparation protocol is a major determinant of how clinical mNGS data should be interpreted and provide a framework for selecting sequencing strategies according to specific diagnostic and biological questions.IMPORTANCEMetagenomic sequencing is increasingly used in infectious disease research and clinical diagnostics, but different library preparation strategies may recover fundamentally different biological signals from the same sample. These signals include not only pathogens but also background microbes, microbial functional activity, and host immune-response patterns. Here, we systematically compared DNA-, RNA-, and total nucleic acid-based metagenomic sequencing libraries using the same clinical samples processed in parallel. We found that the three strategies did not provide equivalent information. RNA-based sequencing generated the most informative single-library view of infection, particularly for RNA viruses, cellular pathogens, functional microbial signals, and host immune-response patterns. DNA-based sequencing was more effective for DNA virus and host genome recovery, whereas the total nucleic acid sequencing workflow evaluated here generally behaved as an intermediate strategy. These findings show that library preparation can substantially influence the interpretation of metagenomic data.

functional characterization↗

PubMed2025

Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.

PURPOSE: Prior studies investigating the genetic architecture of pediatric motor speech disorders (MSDs) have been limited by small sample sizes and an exclusive focus on apraxia. We aimed to identify pathogenic genomic variants associated with MSDs in a large pediatric population referred for exome sequencing (ES). METHODS: We identified pediatric patients with MSDs who had clinical ES between 2012 and 2022. The rate of pathogenic/likely pathogenic (P/LP) findings considered causative of the MSD phenotype was determined and delineated by sex and neurodevelopmental comorbidity. Gene-based burden testing compared the rate of P/LP variants in each gene in MSD cases with a comparison clinical ES cohort. RESULTS: Positive diagnostic results were detected in 527 of 2004 (26.3%) patients with MSDs, with higher diagnostic rates in females and individuals with neurodevelopmental comorbidities. P/LP sequence variants were detected in 262 genes. Gene-based case-referent burden analysis revealed that 30 genes were nominally associated with MSDs, 2 of which (SETBP1 and ADCY5) survived exome-wide correction. CONCLUSION: Over 25% of patients with MSDs were found to harbor P/LP variants in 262 genes, many of which have not previously been associated with MSDs. Potential clinical implications include early implementation of intensive speech therapy for children diagnosed with monogenic causes of MSDs.

Humans↗

PubMed2024

Effect of Metagenomic Next-Generation Sequencing on Clinical Outcomes of Patients With Severe Community-Acquired Pneumonia in the ICU: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) was previously established as a method that can increase the pathogen identification rate in patients with severe community-acquired pneumonia (SCAP). RESEARCH QUESTION: What is the impact on clinical outcomes of mNGS of BAL fluid (BALF) in patients with SCAP in the ICU? STUDY DESIGN AND METHODS: A multicenter randomized controlled open-label clinical trial was conducted in 10 ICUs. Patients were randomized in a 1:1 ratio to undergo BALF assessment with conventional microbiological tests (CMTs) only (ie, the CMT group) or BALF assessment with both mNGS and CMTs (ie, the mNGS group). The primary outcome was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the ICU, whichever occurred first. RESULTS: A total of 349 patients were randomized to treatment between January 1, 2021, and November 18, 2022; 170 were assigned to the CMT group and 179 to the mNGS group. In the intention-to-treat analysis, the time to clinical improvement was better in the mNGS group than in the CMT group (10 days vs 13 days; difference, -2.0 days; 95% CI, -3.0 to 0.0 days). Similar results were obtained in the per-protocol analysis. The proportion of patients with clinical improvement within 14 days was significantly higher in the mNGS group (62.0%) than in the CMT group (46.5%). There was no significant difference in other secondary outcomes. INTERPRETATION: We found that compared with the use of CMTs alone, mNGS combined with CMTs reduced the time to clinical improvement for patients with SCAP. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR; www.chictr.org.cn/index.html; ChiCTR2000037894.

Humans↗

PubMed2026

Age-related genomic characterization and therapeutic targets in Chinese breast cancer: insights from prospective targeted sequencing and clinical data analysis.

BACKGROUND: In China, breast cancer occurs at a much younger age and has a higher recurrence and mortality rate. However, with changes in lifestyle, there has been a trend towards an older age of breast cancer incidence in Chinese women. There is a paucity of large-scale next-generation sequencing cohorts for the analysis of genomic characterization in these populations and the identification of potential therapeutic targets. METHODS: To address this gap, we performed prospective targeted sequencing of tumor and blood samples from Chinese patients and collected detailed clinical information. We then categorized patients into two groups based on age (< 40 years, n = 637; ≥ 40 years, n = 3442) and proceeded to provide comprehensive descriptions of somatic and germline mutations in both groups. RESULTS: The somatic mutation analysis revealed that PIK3CA, FOXA1, and TBX3 mutations were more prevalent in elderly patients. By leveraging the aforementioned mutational characteristics, we employed our institution's FUTURE-SUPER clinical trial, an umbrella study targeting metastatic breast cancer, to confirm the potential benefits of PI3K-AKT-mTOR pathway inhibitors among elderly patients with breast cancer. Furthermore, TP53 and ERBB2 were more likely to be co-mutated in young women. Patients with TP53 and ERBB2 co-mutation tend to have a poorer prognosis, but through investigation of the SPARK cohort, patients carrying the TP53 and ERBB2 co-mutation are more likely to benefit from immune checkpoint inhibitor combination with tyrosine kinase inhibitor therapy. In our study, we observed a higher frequency of mutations in the DNA homology-dependent recombination pathway in young patients with breast cancer, which was associated with an elevated Ki67 index. Additionally, we confirmed a significant prevalence of germline breast cancer susceptibility gene 1 (gBRCA1) mutations in young patients, whereas germline checkpoint kinase 2 (gCHEK2) mutations are more common in elderly patients. CONCLUSIONS: Our study, which makes use of the largest Chinese breast cancer sequencing cohort, sought to characterize the age-related genomic profile of breast cancer patients and identify novel therapeutic opportunities for individuals with breast cancer.

Adult↗

PubMed2026

Molecular DNA enrichment methods for parasite genomic sequencing in clinical samples: a systematic review.

Parasitic diseases such as malaria, Chagas disease, leishmaniases, and helminthiases are major causes of sickness and death in low- and middle-income countries. The high genetic diversity of these pathogens affects virulence, immune evasion, and diagnostic accuracy. Although Whole Genome Sequencing (WGS) is a powerful tool for tracking genetic variants and drug resistance, low parasitemia and the predominance of host DNA limit its application to clinical samples. This study systematically reviewed molecular strategies to improve the recovery of parasite DNA from clinical samples, following PRISMA 2020 guidelines and registered in PROSPERO. Searches of PubMed, Scopus, Web of Science, and LILACS up to December 2025 identified 20 eligible studies, most of which focused on protozoa, particularly Plasmodium spp. The main approaches included hybridization capture, selective whole-genome amplification, host DNA depletion, and in silico enrichment via adaptive sampling. Overall, no single method is suitable for all parasites analyzed; the optimal approach depends on the pathogen, sample type, and research objective. The review emphasizes that parasite DNA enrichment is essential for enabling WGS in clinical settings, underscoring the need for protocol standardization and cost-effectiveness analyses to support public health genomic surveillance.

Adaptive sampling↗

PubMed2024

A comparison of software for analysis of rare and common short tandem repeat (STR) variation using human genome sequences from clinical and population-based samples.

Short tandem repeat (STR) variation is an often overlooked source of variation between genomes. STRs comprise about 3% of the human genome and are highly polymorphic. Some cause Mendelian disease, and others affect gene expression. Their contribution to common disease is not well-understood, but recent software tools designed to genotype STRs using short read sequencing data will help address this. Here, we compare software that genotypes common STRs and rarer STR expansions genome-wide, with the aim of applying them to population-scale genomes. By using the Genome-In-A-Bottle (GIAB) consortium and 1000 Genomes Project short-read sequencing data, we compare performance in terms of sequence length, depth, computing resources needed, genotyping accuracy and number of STRs genotyped. To ensure broad applicability of our findings, we also measure genotyping performance against a set of genomes from clinical samples with known STR expansions, and a set of STRs commonly used for forensic identification. We find that HipSTR, ExpansionHunter and GangSTR perform well in genotyping common STRs, including the CODIS 13 core STRs used for forensic analysis. GangSTR and ExpansionHunter outperform HipSTR for genotyping call rate and memory usage. ExpansionHunter denovo (EHdn), STRling and GangSTR outperformed STRetch for detecting expanded STRs, and EHdn and STRling used considerably less processor time compared to GangSTR. Analysis on shared genomic sequence data provided by the GIAB consortium allows future performance comparisons of new software approaches on a common set of data, facilitating comparisons and allowing researchers to choose the best software that fulfils their needs.

Humans↗

PubMed2025

Coxsackievirus A24 variant whole genome sequencing from clinical samples using a three overlapping amplicons strategy.

In January 2024, the Kenya Ministry of Health issued an outbreak alert following a surge in acute hemorrhagic conjunctivitis (AHC) cases along the Kenyan coast. Our investigations identified coxsackievirus A24 variant (CV-A24v) as the causative agent. In this study, we developed a novel whole genome sequencing assay for CV-A24v, and used it to recover three near complete genomes from the 2024 AHC outbreak in Kenya. This method will support future studies on CV-A24v genomic epidemiology and evolution across Kenya and beyond.

Acute Hemorrhagic Conjunctivitis Kenya↗

PubMed2026

Oxford Nanopore Sequencing of Clinical DNA for Identification and Comparative Genomic Analysis of Erysipelothrix piscisicarius.

The genus Erysipelothrix comprises facultative anaerobic, nonspore-forming, gram-positive bacteria that can cause skin infections and severe diseases such as septicemia and endocarditis in humans. Although E. rhusiopathiae is the primary pathogen, other species may also be involved, necessitating accurate identification. However, 16S rDNA sequencing lacks sufficient resolution to differentiate among Erysipelothrix species. In this study, we used Oxford Nanopore Technology (ONT) to directly sequence low-quality DNA extracted from heart valve tissue of a 66-year-old female patient with a fatal case of septicemia and aortic endocarditis. In contrast to 16S rDNA Illumina sequencing and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), which incorrectly identified the pathogen as E. rhusiopathiae, direct sequencing via ONT precisely identified E. piscisicarius as the cause of infection. About 1.47 Mb genome was retrieved from nanopore direct sequencing. Within the E. piscisicarius genome, we detected genes associated with virulence. Phylogenetic analysis showed that our strain clustered with a human-derived E. piscisicarius strain from China and swine-derived strains from Brazil. In conclusion, this study demonstrated that ONT can be used to sequence low-quality DNA extracted directly from patient specimens, obtain a draft bacterial genome, and reliably distinguish between pathogenic species.

Aged↗

PubMed2026

Genomic Sequencing in Neonatal Encephalopathy and Suspected Hypoxic-Ischaemic Encephalopathy: A Systematic Review.

BACKGROUND: Neonatal encephalopathy (NE) is a major cause of neonatal mortality and long-term neurological disability. Although hypoxic-ischaemic encephalopathy (HIE) is the most common cause, several genetic disorders may mimic or coexist with hypoxic-ischaemic injury. Next-generation sequencing has emerged as a promising diagnostic tool in this setting. This systematic review evaluated the current evidence on genomic sequencing in NE. MATERIAL AND METHODS: A systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in PROSPERO. PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included neonates (≤28 days) with NE, suspected or confirmed HIE, HIE mimics, or unexplained NE who underwent genomic sequencing. Whole-exome sequencing (WES), whole-genome sequencing (WGS), clinical exome sequencing (CES), rapid genomic sequencing, and targeted next-generation sequencing panels were considered. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Seven studies met the inclusion criteria. Considerable heterogeneity was observed regarding patient selection, sequencing strategies, and reported outcomes. Among diagnostic sequencing studies, diagnostic yield ranged from 23.5% to 53.1%. Pathogenic and likely pathogenic variants were identified in genes associated with developmental and epileptic encephalopathies, metabolic disorders, mitochondrial diseases, and neurodevelopmental syndromes, including SCN2A, KCNQ2, CACNA1A, STXBP1, PTPN11, BCOR, MMUT, COQ2, and GBE1. Genomic sequencing frequently refined or changed the initial diagnosis, improved prognostic assessment and genetic counselling, and, in selected cases, guided disease-specific treatment. One study investigated genetic susceptibility to hypoxic-ischaemic injury rather than diagnostic sequencing. CONCLUSIONS: Genomic sequencing provides clinically meaningful diagnoses in a substantial proportion of neonates with unexplained NE or atypical HIE presentations. Current evidence supports integrating genomic sequencing into the diagnostic evaluation of selected infants, although larger prospective studies are needed to define its optimal timing, clinical utility, and cost-effectiveness.

Humans↗

PubMed2026

First nationwide full-genome characterisation of human-derived Andes virus in Chile: a retrospective genomic epidemiology study.

BACKGROUND: Andes virus (ANDV) is the only hantavirus known to transmit between humans and causes hantavirus cardiopulmonary syndrome in Chile and Argentina. In Chile, ANDV genomic diversity remains incompletely characterised. This study aimed to characterise the genetic diversity, geographical structure, and molecular signatures of ANDV using human clinical samples collected over a 13-year period (2011-24). METHODS: We conducted a retrospective genomic epidemiology study of ANDV infections in Chile. Clinical samples from patients with confirmed ANDV, collected between March 9, 2011, and June 27, 2024, were analysed and sequenced. Clinical and epidemiological data were obtained from diagnostic laboratories and surveillance programmes. Consensus sequences for the S, M, and L segments were generated, and genetic clustering and divergence were assessed using phylogenetic inference and variant calling. FINDINGS: We analysed clinical samples from 58 infected individuals and identified two major genomic variants of ANDV with distinct geographical distributions, defined by regionally structured patterns of nucleotide and amino acid substitutions across the S, M, and L segments: ANDV Chi-North (central Chile) and ANDV-South (southern Chile). No consistent clustering by clinical severity was observed, and no recurrent non-synonymous substitutions were uniquely associated with severe disease. Substitutions previously associated with person-to-person transmission in outbreaks in Argentina were not consistently observed in Chilean sequences, including in four person-to-person transmission cases. Although some substitutions described in ANDV-like viruses were present in the Chi-North lineage, this lineage remained phylogenetically distinct and geographically restricted to central Chile. INTERPRETATION: To our knowledge, this study provides the first nationwide genomic characterisation of human-derived ANDV in Chile. The identification of geographically structured variants indicates that ANDV diversity in Chile is driven by regional diversification rather than clinical outcome. The absence of consistent amino acid signatures associated with disease severity or person-to-person transmission suggests that these phenotypes are unlikely to be explained by viral genetic variation alone. These findings refine current understanding of ANDV evolution and highlight the need for continued integrated genomic surveillance in endemic regions. FUNDING: Agencia Nacional de Investigación y Desarrollo de Chile and National Institutes of Health.

Humans↗

PubMed2026

Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy.

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review. METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases. RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays. CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.

ARV1↗

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

Emergence of ceftazidime-avibactam resistance mediated by KPC variants KPC-71 and KPC-78 in ST463 Pseudomonas aeruginosa.

UNLABELLED: Pseudomonas aeruginosa is a well-recognized opportunistic pathogen and a leading cause of healthcare-associated infections. The shrinking effectiveness of available antimicrobial therapies has intensified the global threat posed by carbapenem-resistant P. aeruginosa (CRPA). Here, we elucidate the mechanisms of ceftazidime-avibactam (CZA) resistance mediated by the rare KPC variants, KPC-71 and KPC-78, identified during the treatment of CRPA infections. Two CZA-resistant P. aeruginosa strains, SY-206885 and HZ-231016032, were isolated from critically ill male patients with severe pneumonia. Whole-genome sequencing assigned both isolates to the high-risk sequence type 463 (ST463). Isolate SY-206885 harbors the blaKPC-71 gene, while HZ-231016032 carries blaKPC-78. Cloning and expression of these genes in P. aeruginosa PAO1 conferred a marked increase in the CZA minimum inhibitory concentration. Notably, expression of KPC-71 or KPC-78 conferred CZA resistance while simultaneously reducing carbapenem hydrolytic activity, a trade-off previously described for some KPC variants but still rarely documented in P. aeruginosa. Structural analysis and kinetic profiling showed that, relative to wild-type KPC-2, both KPC-71 and KPC-78 exhibited reduced catalytic turnover but increased substrate affinity for ceftazidime, together with significantly weakened binding to avibactam. In addition, elevated expression of MexAB-OprM and AmpC-related determinants in the clinical isolates likely further enhanced the high-level CZA resistance phenotype. These findings highlight the capacity of the ST463 CRPA lineage to evolve CZA resistance through KPC structural diversification under antimicrobial pressure and underscore the need for close surveillance during therapy. IMPORTANCE: In this study, we report the detection of the uncommon KPC variants KPC-71 and KPC-78 in clinical sequence type 463 (ST463) carbapenem-resistant Pseudomonas aeruginosa isolates exhibiting resistance to ceftazidime-avibactam (CZA). We demonstrate that CZA resistance is driven by specific structural alterations-a serine insertion between residues 182 and 183 or a D179A substitution within the Ω-loop-that reshape the functional balance of the KPC enzyme. These changes appear to create an evolutionary trade-off by improving ceftazidime recognition while weakening avibactam-mediated inhibition. Given the widespread dissemination of the ST463 lineage in China, the emergence of these variants highlights the urgent need for clinicians to monitor for CZA resistance development during therapy. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as ChiCTR2500105846.

Ceftazidime↗

PubMed2025

Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders.

BACKGROUND: Rare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs. METHODS: We leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects. RESULTS: Prematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p = 7.83 × 10-5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we showed that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically influenced parental traits or confounders, rather than direct genetic effects in the child, and that a monogenic diagnosis modifies this association. CONCLUSIONS: Our findings emphasise the importance of considering environmental factors like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

Humans↗

PubMed2026

Clinical and Genetic Spectrum of ACO2-Linked Dominant Optic Atrophy.

IMPORTANCE: Aconitase 2 (ACO2) gene variants are one of the most frequent causes of dominant optic atrophy (DOA). However, the associated phenotypes and genotypes still lack proper characterization. OBJECTIVE: To characterize the clinical and genetic spectrum of ACO2-related DOA and evaluate genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case series to describe the ophthalmological examination of novel DOA cases with a heterozygous ACO2 variant. Data were collected from 13 reference centers in ophthalmology from France and Great Britain between January 2021 and September 2025. Included participants were those patients with OA and confirmed heterozygous or compound heterozygous ACO2 variants. EXPOSURES: DOA cases with a heterozygous ACO2 variant. MAIN OUTCOMES AND MEASURES: Positive molecular diagnosis for ACO2 variants by next-generation sequencing, clinical examination including age at diagnosis, sex, best-corrected visual acuity (BCVA), retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness, visual field mean deviation (MD), and fundus examination. RESULTS: Data for 55 patients (median [IQR] age at diagnosis for 45 patients, 24 [8-51] years; 33 male [67%]) from 37 families with ACO2 variants were compiled. Analyses were conducted on 49 patients who were strictly heterozygous or compound heterozygous with the c.220C>G benign variant. Clinical data disclosed a high variability of severity, from pauci-symptomatic up to legal blindness. Median BCVA was 0.46 logMAR (Snellen equivalent, 20/63; IQR 0.00-0.89; n = 45). Four patients exhibited retinal abnormalities: 3 displayed a foveopathy, and 1 had retinitis pigmentosa. There were 12 previously unreported variants (to the authors' knowledge), including the deletion of ACO2 exon 9. No correlation between BCVA and sex, age at diagnosis (Spearman ρ = -0.19; 95% CI, -0.45 to 0.07), or variant type (Kruskal-Wallis test P =.33) was found, but there was a correlation between BCVA and RNFL (Spearman ρ = -0.74; 95% CI, -0.85 to -0.54), GCL (Spearman ρ = -0.60; 95% CI, -0.79 to -0.30), and MD (Spearman ρ = -0.65; 95% CI, -0.89 to -0.31). RNFL correlated with GCL (Spearman ρ = 0.69; 95% CI, 0.42-0.87) and MD (Spearman ρ = 0.57; 95% CI, 0.14-0.85); age at diagnosis correlated with GCL (Spearman ρ = -0.37; 95% CI, -0.63 to -0.03). CONCLUSIONS AND RELEVANCE: Results of this case series reveal the high clinical heterogeneity among patients with ACO2-related DOA and demonstrated that some of these patients can also exhibit retinal abnormalities. In addition, there was a deletion of an entire ACO2 exon, emphasizing the potential importance of searching for large genomic rearrangements in patients without a molecular diagnosis. These findings support further studies to explain clinical variability, as no genotype-phenotype correlation was encountered.

Humans↗