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PubMed2025

Clinical utility of comprehensive genomic profiling test for colorectal cancer: a single institution prospective observational study.

PURPOSE: Next-generation sequencing (NGS) has revolutionized cancer treatment by enabling comprehensive cancer genomic profiling (CGP) to guide genotype-directed therapies. While several prospective trials have demonstrated varying outcomes with CGP in patients with advanced solid tumors, its clinical utility in colorectal cancer (CRC) remains to be evaluated. METHODS: We conducted a prospective observational study of CGP in our hospital between September 2019 and March 2024. Overall survival (OS) of the patients who received CGP-based therapy and those did not was compared, and genomic variables associated with OS were evaluated. RESULTS: A total of 100 patients with CRC underwent CGP using four platforms. The median patient age was 67 years, and most had a good performance status. The most frequent genomic alterations were TP53 (82%), APC (82%), and KRAS (55%). Actionable mutations such as ERBB2 amplification and BRAF V600E were identified in some patients, and 9% received CGP-based therapy, including immune checkpoint inhibitors for tumor mutational burden-high or microsatellite instability-high tumors. Patients receiving CGP-based therapy had longer OS from expert panel discussion (16.0 vs. 10.8 months) compared to those who did not. Alterations in TP53, SMAD4, and NF1 were associated with worse OS. Interestingly, PTEN mutations were linked to improved survival. TP53 alterations were more common in left-sided CRC. CONCLUSION: Although some patients with CRC received CGP-guided therapy, a statistically significant survival benefit was not observed. However, TP53 and SMAD4 mutations were identified as negative prognostic markers, indicating their potential as targets for future drug development.

Humans↗
PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗
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

Multigene testing to guide clinical adjuvant decisions in breast cancer: An overview focused on the assessment of the quality of evidence with the grading of recommendations assessment, development and evaluation (GRADE) approach.

Multigene tests have emerged as valuable tools in guiding adjuvant chemotherapy decisions for patients with ER-positive/HER2-negative early breast cancer. This study applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence supporting the clinical utility of these tests. We focused on OncotypeDX® and MammaPrint®, the two tests evaluated in prospective randomized trials. The analysis was structured around the clinical question of whether these tests should be recommended for patients with ER-positive, HER2-negative, lymph node-negative or up to 3 lymph nodes-positive invasive breast cancer to guide adjuvant chemotherapy decisions. Our findings reveal that OncotypeDX® demonstrates high clinical utility in sparing chemotherapy for older/postmenopausal patients, with convincing quality of evidence for both node-negative and node-positive patients. The clinical utility of MammaPrint® appears more controversial, with conflicting results between node-negative and node-positive patients. A particularly critical aspect remains the clinical usefulness of these tests in younger/premenopausal women, where the benefit of adjuvant chemotherapy was shown but with potential biases in the study designs. Despite the established role of multigene tests and their availability in Italy since 2021, their uptake in clinical practice remains suboptimal. This formal appraisal of the clinical utility of genomic tests, particularly OncotypeDX®, aims to reinforce their fundamental role in personalizing adjuvant treatment decisions and optimizing resource allocation. The study underscores the importance of these tests in sparing unnecessary chemotherapy toxicities and costs, while emphasizing the need for further research to address remaining uncertainties, especially in younger patient populations.

Humans↗
PubMed2026

Moebius-Plus Phenotype With Positive RCEM Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling.

Moebius syndrome (OMIM #157900) is a rare congenital cranial dysinnervation disorder characterized by abducens (CN VI) and facial (CN VII) nerve palsies with variable craniofacial and limb anomalies. Despite advances in genomic testing, the majority of patients remain genetically unexplained. Episignature testing, which detects syndrome-specific DNA methylation patterns, has emerged as a complementary diagnostic tool for conditions with shared developmental mechanisms. We describe an 8-month-old male born prematurely with bilateral clubfoot, craniofacial dysmorphism, feeding difficulty requiring gastrostomy tube placement, and respiratory failure requiring tracheostomy. Neuroimaging demonstrated absence of bilateral abducens and facial nerves with pontocerebellar hypoplasia, supporting a clinical diagnosis of Moebius syndrome. Extensive genetic evaluation, including genome sequencing and targeted testing for hypotonia and hypoventilation syndromes, was nondiagnostic. Episignature analysis revealed a moderately positive methylation signature consistent with a recurrent constellation of embryonic malformation (RCEM), concordant with two of three previously validated RCEM classifier models. To our knowledge, this is the first report of a patient with a positive RCEM episignature and Moebius syndrome, suggesting a common embryologic pathway. Episignature testing may represent a valuable diagnostic tool in patients with Moebius syndrome and related craniofacial-limb malformation spectra when conventional genomic testing is unrevealing.

RCEM↗
PubMed2026

The role of pathology laboratories in integrating genetic testing into Australian primary care: an implementation science perspective.

As genomic testing moves into mainstream healthcare, non-genetic healthcare professionals, including general practitioners (GPs), play a critical role as gatekeepers to genetic services. Laboratories are essential in supporting this transition by providing not only high-quality genetic tests but also point-of-care tools, educational materials and clinical guidance to support their use. This study aimed to explore how these tools and supports are conceptualized, developed, implemented and evaluated and how laboratories integrate them into their relationships with GPs, an essential process for paving the way toward better use of genomics in primary care. A qualitative study design was employed using semi-structured, in-depth interviews with representatives from genetic laboratories across Australia. The Consolidated Framework for Implementation Research (CFIR) guided deductive content analysis of data. Findings spanned the four CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting and Implementation Process) across 34 constructs. Participants reported that laboratories viewed point-of-care tools and resources as essential responses to persistent genomic knowledge gaps among GPs. Development of evidence-based, practice-driven and adaptable resources was supported and rewarded within laboratory organisations. A strong culture of clinical responsibility and implementation readiness, combined with robust networks and communications, enabled timely support for GPs. Gaps identified included lack of implementation planning, misalignments between laboratory-developed resources and GPs' real-world needs and inadequate mechanisms for obtaining GPs' feedback, which made evaluation problematic. By applying an implementation science framework, these findings provide insights for future efforts to build and sustain the provision of point-of-care tools and support, ultimately improving the integration of genomics in primary care.

Journal Article↗
PubMed2024

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.

PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program. METHODS: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. CONCLUSION: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Humans↗
PubMed2026

Next-Generation Sequencing Completion and Timeliness Using a Reflex Testing Protocol for Patients with Stage II to IV Nonsquamous Non-Small Cell Lung Cancer.

BACKGROUND: Next-generation Sequencing (NGS) is critical for providing treatment recommendations across multiple stages of non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not undergo testing. This study evaluated the completion rates and timeliness of NGS in patients with stage II to IV NSCLC at a single academic institution with a reflex NGS testing protocol. METHODS: Patients with stage II to IV nonsquamous NSCLC (ns-NSCLC) diagnosed between 2015 and 2022 were identified retrospectively. A reflex, tissue-based testing protocol was initiated in 2015 using in-house NGS. Pyrosequencing was performed if NGS failed. RESULTS: 501 patients were included: 75 (15.0%) with stage II, 82 (16.4%) with stage III, and 344 (68.6%) with stage IV ns-NSCLC. Tissue NGS was completed in 380 (75.8%) patients and 465 (92.8%) completed some tissue-based genomic testing when including pyrosequencing. Median time from biopsy to NGS was 17.0 days (range, 6-61 days). 61.0% of patients had NGS results prior to a first treatment of any type and 88.4% had tissue NGS results prior to systemic therapy. Among stage IV patients with completed NGS, median overall survival was 2.27 years for patients with NGS results prior to first treatment compared to 1.08 years for patients without NGS results prior to treatment initiation (P = .04). CONCLUSIONS: Implementation of an in-house, reflex NGS testing protocol enabled rapid genomic profiling in a high proportion of patients with stage II to IV ns-NSCLC. NGS completion prior to receiving first-line therapy was associated with improved survival compared to completion after first line treatment in stage IV patients.

Humans↗
PubMed2026

Association of FOXC1 Duplications With Juvenile Open-Angle Glaucoma.

IMPORTANCE: While FOXC1 single-nucleotide variants and deletions are well-established causes of Axenfeld-Rieger syndrome, few FOXC1 duplications have been reported. This study investigated families with duplications encompassing the FOXC1 gene to refine the associated phenotypic spectrum and contribution to glaucoma. OBJECTIVE: To investigate the prevalence and phenotype of FOXC1 duplications in 2 large glaucoma registries. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational genetic cohort study included participants recruited from the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) and the Massachusetts Eye and Ear (MEE) cohort from 2008 through 2025. Participants with glaucoma, and available relatives, underwent genomic testing to identify duplications encompassing FOXC1 using exome sequencing and genotyping arrays (ANZRAG) or whole-genome sequencing (MEE). Data analyses were conducted from 2022 through 2025. MAIN OUTCOMES AND MEASURES: Prevalence of FOXC1 duplications, age at glaucoma onset, and phenotype, including ocular and systemic features. RESULTS: Twenty individuals from 10 families (50% female and 50% male; 70% self-described as broadly European [Australian/British, British, English/German, English/Polish, European, or Scottish], 25% as Asian [Chinese or Filipino], and 5% as Latin American [Salvadoran]) were identified with FOXC1 duplications. All genetically tested individuals were diagnosed with glaucoma, demonstrating high penetrance. Seventeen individuals were referred with juvenile open-angle glaucoma (JOAG), 1 with primary open-angle glaucoma, 1 with primary congenital glaucoma, and 1 with anterior segment dysgenesis. The diagnosis of 4 individuals from 1 family with ectropion uveae was revised to anterior segment dysgenesis. Systemic features were reported for 2 participants (10.5%), including subtle dental findings and mild facial dysmorphism. Duplications encompassing FOXC1 were among the most common monogenic contributors to JOAG. In the ANZRAG group, they accounted for 13.5% (95% CI, 6.7%-25.3%) of JOAG probands with a genetic diagnosis, second to MYOC (53.8%; 95% CI, 40.5%-66.7%). In the MEE group, FOXC1 duplications accounted for 9.5% (95% CI, 2.7%-28.9%) of JOAG probands with a genetic diagnosis. CONCLUSIONS AND RELEVANCE: These findings suggest FOXC1 duplications are an underrecognized, highly penetrant, but variably expressive, genetic variation associated with JOAG. Findings for the relatively modest number of individuals in the retrospective study were associated with wide confidence intervals. This limitation is often inherent to studies of JOAG, a rare condition for which individual genetic variants account for only a subset of cases. Despite this, the findings highlight the genetic heterogeneity of JOAG and support the potential importance of considering routine genetic copy-number variant analysis for individuals with JOAG.

Humans↗
PubMed2025

Uterine Sarcomas With Recurrent KDM2B Gene Fusions: Three Cases of a Possible Novel Subtype of High-Grade Endometrial Stromal Sarcoma.

The advent of widespread genomic testing of uterine mesenchymal tumors has led to novel insights into the biology of these diverse tumors, and many genomically defined entities have been described in recent years. During a larger study of endometrial stromal sarcomas and unclassified uterine sarcomas, we identified 3 tumors harboring KDM2B gene fusions. Patients were 32, 61, and 67 years old, and all initially underwent incomplete sampling via laparoscopic myomectomy (n = 1), laparoscopic biopsy (n = 1), or hysteroscopic myomectomy (n = 1). One patient's tumor was densely adherent to the pelvic sidewall; she was treated with chemotherapy and died of widely metastatic disease at 29 weeks. Another underwent a subsequent recent hysterectomy with the tumor confined to the uterus and minimal follow-up to date. The final patient refused further treatment and was alive at 28 weeks, although the status of the disease progression was unknown. On microscopic examination, 2 tumors showed infiltrative borders, whereas interface with the myometrium was not present in the third. The tumors were variably cellular with alternating hypercellular and hypocellular zones in a myxoid to loosely collagenous stroma. The hypercellular areas contained round to ovoid cells in diffuse (n = 3) and sex cord-like arrangements, including cords (n = 3), nests (n = 2), and tubules (n = 1); 2 also contained occasional spindled cells arranged in vague fascicles. These cells showed moderate atypia with open chromatin, numerous mitoses (8, 24, and 25 per 10 high-power fields), and frequent apoptosis. The hypocellular areas contained sparse, ovoid-to-spindled cells with minimal atypia. All tumors were diffusely positive for cyclin D1, whereas BCL6 corepressor was diffusely positive in 1 and negative in 2; desmin and caldesmon were negative in all 3 neoplasms. All harbored KDM2B gene fusions; partner genes included EPC1, EP400, and CITED1. MDM2 amplification was also noted in 2. Clustering analysis based on RNA expression profiling revealed tight clustering of all 3 tumors within the broad group of high-grade endometrial stromal sarcomas. Based on the overall clinicopathologic and genomic features, we suggest that these tumors may represent a novel subtype of uterine sarcoma and may be best classified as high-grade endometrial stromal sarcoma, although additional confirmatory studies are needed.

Humans↗
PubMed2026

Phylogeographic analysis of Staphylococcus nepalensis reveals global occurrence of antimicrobial-resistant lineages carrying the sal(E) resistance gene.

BACKGROUND: Staphylococcus nepalensis is an emerging species first described in 2003 from the respiratory tract of goats in Nepal. We report the identification of S. nepalensis of a hypersaline lagoon in Brazil, along with in-depth phylogeographical and resistome analysis of publicly available genomes. METHODS AND RESULTS: During a local survey from hypersaline aquatic environments in Rio de Janeiro, Brazil, two staphylococcal strains were recovered, designated as COLB and AM1. These isolates were subjected to antimicrobial susceptibility testing, genomic sequencing, and comprehensive phylogenomic analyses. Genomic analysis confirmed the taxonomic identity of COLB and AM1 as S. nepalensis. Both isolates harbored the sal(E) conferring resistance to pleuromutilins and streptogramin A, whereas tet(K) conferring to tetracyclines. Additionally, AM1 carried lnu(A), consistent with the reduced susceptibility to clindamycin (MIC = 2 µg/mL) relative to COLB. Genes associated with arsenic and copper tolerance, and the replicons rep7a and rep19c, were confirmed. Phylogenomic analysis indicated that COLB and AM1 were clonally related (1 cgSNP-difference) but distinct from global isolates. Phylogeographic analysis revealed wide geographic occurrence, with some lineages carrying blaZ and mecA associated with beta-lactamase production and methicillin resistance, respectively. Strikingly, sal(E) is conserved across all S. nepalensis genomes. CONCLUSIONS: The findings confirm the presence of S. nepalensis in South America as early as 2016 and documented among available genomes from environmental, human, and animal-associated sources. Furthermore, reveal the circulation of some lineages carrying clinically relevant antimicrobial genes, underscoring the importance of accurate species identification and continuous genomic surveillance and potential One Health relevance.

Phylogeography↗
PubMed2024

Genomes for Nurses: Understanding and Overcoming Barriers to Nurses Utilizing Genomics.

Background: Genomic testing is an increasingly important technology within pediatric oncology that aids in cancer diagnosis, provides prognostic information, identifies therapeutic targets, and reveals underlying cancer predisposition. However, nurses lack basic knowledge of genomics and have limited self-assurance in using genomic information in their daily practice. This single-institution project was carried out at an academic pediatric cancer hospital in the United States with the aim to explore the barriers to achieving genomics literacy for pediatric oncology nurses. Method: This project assessed barriers to genomic education and preferences for receiving genomics education among pediatric oncology nurses, nurse practitioners, and physician assistants. An electronic survey with demographic questions and 15 genetics-focused questions was developed. The final survey instrument consisted of nine sections and was pilot-tested prior to administration. Data were analyzed using a ranking strategy, and five focus groups were conducted to capture more-nuanced information. The focus group sessions lasted 40 min to 1 hour and were recorded and transcribed. Results: Over 50% of respondents were uncomfortable with or felt unprepared to answer questions from patients and/or family members about genomics. This unease ranked as the top barrier to using genomic information in clinical practice. Discussion: These results reveal that most nurses require additional education to facilitate an understanding of genomics. This project lays the foundation to guide the development of a pediatric cancer genomics curriculum, which will enable the incorporation of genomics into nursing practice.

Humans↗
PubMed2026

Cre-loaded integrase-defective lentiviral vectors for targeted cassette exchange in CHO cells.

Genome-modifying enzymes, such as recombinases and CRISPR-associated nucleases, enable targeted gene insertion when delivered transiently to minimize off-target effects. Precise genome engineering requires controlled enzyme activity, as well as efficient donor DNA transfer. Integrase-defective lentiviral vectors (IDLVs) provide a promising platform for transient episomal DNA transfer; however, their integration efficiency depends on complementary genome-targeting strategies. Here, we engineered Cre-loaded IDLVs (Cre-IDLVs) that co-package lentiviral vector genomes together with bioactive Cre recombinase. Cre was inserted into the Gag region of an integrase-defective gag-pol construct, allowing for efficient encapsidation and protease-mediated release during virion maturation without compromising the viral titer. The resulting particles carried donor cassettes flanked by heterospecific loxP sites. When applied to CHO founder cells harboring compatible genomic loxP landing pads, Cre-IDLVs efficiently mediated recombination-mediated cassette exchange, producing the highest number of G418-resistant colonies among the plasmid ratios tested. Genomic PCR and sequencing confirmed precise locus-specific insertion without detectable random integration in the analyzed clones. These findings establish Cre-IDLVs as a streamlined dual-delivery platform that couples transient recombinase activity with episomal donor DNA transfer. This hybrid lentiviral strategy provides a programmable approach for controlled and site-specific genome modification in mammalian cells.

Integrases↗
PubMed2026

Feasibility, reliability, and clinical value of genomic assay on pre-therapeutic biopsy for endocrine receptor-positive HER2-negative early breast cancer.

Endocrine receptor-positive (ER+) and HER2-negative breast cancer (BC) represents approximately 80% of all BCs. Most patients are treated with upfront surgery; however, 15%-30% will develop late recurrences. Genomic assay indication is usually based on postoperative pathological data including histology subtype, tumor size, lymph node status, SBR grade, and Ki67. Performing genomic testing on core needle biopsy specimens prior to surgery may offer several advantages. In this manuscript, we assess the feasibility, reliability, utility, and potential benefits of such genomic analyses performed on core needle biopsies. Several factors may lead to proposing genomic assay analysis on biopsy: (1) optimization of the patient pathway by reducing time to therapeutic decision-making, (2) predicting response to neoadjuvant chemotherapy (NAC) or neoadjuvant endocrine therapy (NET), and (3) refining prognostic assessment to guide adjuvant chemotherapy decisions in patients for whom axillary surgery is not planned. Given the feasibility and reliability of genomic assay on core needle biopsies, it can be suggested that this practice may become more common in the near future. Knowledge of the evolutive risk determined by the result of genomic assay, as well as clinicopathological characteristics, allows more precise personalization of the therapeutic strategy, including the choice between upfront surgery and neoadjuvant therapy, the selection of systemic treatments, and decision-making in the absence of axillary staging.

breast cancer↗
PubMed2026

Prenatal Phenotypic Features of Five Fetal Cases With RNU4ATAC-Associated Microcephalic Osteodysplastic Primordial Dwarfism Type I.

OBJECTIVE: To present the prenatal sonographic features, genomic findings, and pregnancy outcomes of fetuses with biallelic pathogenic RNU4ATAC variants linked to microcephalic osteodysplastic primordial dwarfism type I (MOPD1). METHODS: This retrospective case series includes five prenatal cases with MOPD1. Diagnoses were established by prenatal ultrasound and genetic testing. Genome sequencing (GS) or targeted exome sequencing (ES) detected the variants either prenatally or after termination of pregnancy (TOP). Clinical data including parental demographics, ultrasound findings, and pregnancy outcomes were collected. RESULTS: All fetuses presented with consistent anomalies on ultrasound including intrauterine growth restriction (IUGR), microcephaly, agenesis of the corpus callosum (ACC), intracranial cysts, lissencephaly, and micrognathia. IUGR was the earliest anomaly detected in all five cases. Prenatal ultrasound findings suggestive of skeletal dysplasia were identified in one case. All cases carried biallelic pathogenic RNU4ATAC variants associated with MOPD1. TOP was chosen in four cases. One fetus was delivered at 39 + 1 weeks with genetic diagnosis confirmed at 27 weeks. CONCLUSION: IUGR, microcephaly and ACC can be detected in fetuses with MOPD1 at around 18 weeks of gestation. Interestingly, skeletal dysplasia was not a consistent prenatal finding. Variants in the non-coding RNU4ATAC gene need to be detected by GS or targeted approaches beyond standard ES.

Humans↗
PubMed2026

CanVar-UK: A collaborative platform for germline interpretation in cancer susceptibility genes.

Germline variants in cancer susceptibility genes (CSGs) are typically inherited rather than arising de novo. Hence, wide cascade testing of families across geographies is common, meaning consistency in variant classification is particularly critical. Variant interpretation requires collation of variant-level data from diverse sources, as well as assembly of comprehensive clinical data, often necessitating sharing of information between genomic testing centers. Here, we describe CanVar-UK, a freely accessible web platform bespoke designed to support interpretation of germline CSG variants. CanVar-UK contains variant-level data for over 1.1 million single-nucleotide variants (SNVs), comprising all possible coding SNVs in 116 established CSGs. The data sources with which variants are annotated include in silico scores from 11 clinically relevant tools, population allele frequencies from gnomAD v4.1, case counts from multiple cohorts, including National Health Service (NHS) clinical laboratory testing, variant-level readouts from 47 selected functional and splicing datasets across 19 CSGs, genetic epidemiology studies, and live linkage to existing consensus classifications in the ClinVar database. The diagnostic discussion forum is only available to registered diagnostic scientist users. Through this, a variant-tagged email message can be dispatched in real time across the diagnostic forum community of >1,500 users, with all exchanges and classifications captured and stored in the platform. Already widely used by NHS diagnostic clinical scientists in the UK, CanVar-UK has a rapidly growing international diagnostic user base (>800 UK and >600 non-UK registered users). Survey of the NHS diagnostic user community illustrates the wide-ranging utility of CanVar-UK within their clinical workflows for interpretation of germline CSG variants.

Journal Article↗
PubMed2026

Genomic and phenotypic characterization of Klebsiella pneumoniae phage KP Ø1: a novel lytic Slopekvirus targeting uropathogenic multidrug-resistant Klebsiella pneumoniae.

The rise of multidrug-resistant (MDR) uropathogenic gram-negative bacteria (GNB) necessitates the development of alternative therapeutic strategies. This study aimed to isolate, phenotypically characterize, and perform whole-genome sequencing of the bacteriophage demonstrating the broadest host range against MDR uropathogens. Fifty MDR GNB isolates were screened for lytic phages. The most promising candidate, Klebsiella pneumoniae phage KP Ø1, was characterized using plaque assay, Transmission Electron Microscopy (TEM), and pH/thermal stability testing. Genomic characterization was performed via whole-genome sequencing (WGS), with functional annotation and lifestyle prediction using PhaBOX and PhageScope software. Klebsiella pneumoniae was the most prevalent MDR uropathogen. Klebsiella pneumoniae phage KP Ø1 exhibited a 50% host range and high lytic titer (10⁸ PFU/mL). TEM revealed an icosahedral head and short contractile tail. Genomic characterization by WGS revealed that Klebsiella pneumoniae phage KP Ø1 possesses a 174,591 bp double-stranded deoxyribonucleic acid (dsDNA) genome containing 274 predicted open reading frames (ORFs). No lysogeny-related genes, toxins, or antibiotic resistance markers were detected, confirming its strictly lytic nature and supporting its potential as a candidate for phage therapy applications. The phage remained stable (10⁸ PFU/mL) across temperatures of - 20 °C to 50 °C; supporting its suitability for long-term biobanking and suggesting potential activity at physiological temperature, and across a pH range of 7-9. Klebsiella pneumoniae phage KP Ø1 is a novel, obligately lytic Slopekvirus whose genomic architecture, stability profile, and absence of lysogeny-associated, virulence, and antimicrobial resistance genes ( AMR) collectively support its candidacy for further preclinical evaluation as a phage therapy agent against uropathogenic MDR Klebsiella pneumoniae.

Klebsiella pneumoniae↗
PubMed2026

Examining gaps in institutional policies for clinical genomic data sharing: A cross-jurisdictional study.

The sharing of data generated by clinical genetic and genomic testing without explicit consent is important for timely diagnosis and treatment. While many jurisdictions permit the sharing of identifiable data for direct clinical care, institutional policies vary in how clearly they specify key elements, including when sharing is permitted, what data are covered, and what safeguards apply. Greater clarity around these elements may support responsible data sharing while balancing timely care with transparency and appropriate protections. We conducted a mixed-methods content analysis of data-sharing and privacy policies from 33 clinical genomic institutions across 17 countries and regions. Using a predefined analytical framework, we assessed how policies document key governance elements relevant to sharing without explicit consent. Two independent reviewers extracted information about clinical contexts, data types, justifications, and protections. Although 70% of institutions described circumstances permitting data sharing without explicit consent, most policies did not clearly define the scope or governance of such sharing. Policies also rarely distinguished clinical from research or secondary use and inconsistently specified privacy and security safeguards. While sharing was commonly justified for clinical care (78.3%) or testing services (43.5%), data recipient roles and onward-sharing expectations were often left undefined. This uneven documentation could make it difficult for clinical teams and institutional decision-makers to identify and justify decisions about what is permitted and under what conditions. A guidance framework specifying core governance elements and corresponding protections could help institutions communicate their governance choices more clearly and support comparable baseline practices for responsible data sharing.

Information Dissemination↗