Genet Med. 2026 Mar 16:102551. doi: 10.1016/j.gim.2026.102551. Online ahead of print. ABSTRACT PURPOSE: Biallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-related neuroimmunological syndrome and explore the gene’s developmental role using vertebrate models. METHODS: 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients were studied. Clinical features were analysed and functional studies were conducted using knockout models in Danio rerio and Xenopus tropicalis. RESULTS: Clinical features included developmental delay, intellectual disability, progressive microcephaly, cortical visual impairment or blindness, epilepsy, and frequent occipital-predominant brain abnormalities. Almost half suffered from infections, mainly affecting their respiratory tract related to epilepsy and aspiration. Although the majority had normal lymphocyte subsets and serum immunoglobulins, T-cell receptor excision circles and naïve T-lymphocyte counts were consistently low. The Xenopus model mirrored growth and eye defects seen in humans, while zebrafish exhibited no overt malformations but showed seizure-like behaviour in Phenothiazine assays. CONCLUSIONS: DIAPH1 is critical for neurodevelopment, immune regulation, and DNA repair. The DNA repair defect may influence susceptibility to infection, lymphoma, or treatment-related toxicity. Although absolute T-cell numbers are not consistent with SCID, impaired T-cell maturation suggests these patients could be identified by TREC newborn screening before neurological symptoms develop. PMID:41860019 | DOI:10.1016/j.gim.2026.102551

N Engl J Med. 2026 Mar 12;394(11):1142. doi: 10.1056/NEJMc2518638. NO ABSTRACT PMID:41812208 | DOI:10.1056/NEJMc2518638

Eur J Pediatr. 2026 Mar 11;185(4):175. doi: 10.1007/s00431-026-06801-0. ABSTRACT Alazami syndrome is a neurodevelopmental disorder characterized by postnatal growth retardation, moderate to severe intellectual disability, and facial dysmorphology. It is caused by biallelic variants in the transcriptional regulator La ribonucleoprotein 7 (LARP7), where frameshift variants accounted for the majority of cases. The current study presents 7 new patients, including 3 males and 4 females from 3 unrelated families. Careful and thorough clinical examination identified novel oro-dental disease abnormalities, including a prominent premaxilla and enamel defects. The detected variants (c.1113_1116del, c.997 + 2T > C and c.518T > C) were not reported in the previous studies. The substitution c.518T > C represented the second missense variant to be identified in patients with Alazami syndrome. Male patients from the three families fulfilled ≥ 2 clinical warning signs of primary immunodeficiency. Lymphocyte subset counts and immunoglobulin levels were estimated in patients from two families. The values were within reference ranges, with only minor non-significant alterations in cytotoxic T-cell counts. A functional assay of B lymphocyte response was performed in one family, demonstrating impaired Streptococcus pneumoniae IgG antibody production following Pneumovax vaccination in the male patient, while his female sibling mounted an adequate response. In conclusion, the disease has a wide range of symptoms, which vary greatly among the affected patients. Our study expanded the clinical and molecular spectrum of the disorder and highlighted immunodeficiency as an underrecognized disease feature, potentially with a male sex predilection. PMID:41811398 | DOI:10.1007/s00431-026-06801-0

bioRxiv [Preprint]. 2026 Mar 2:2026.02.27.708546. doi: 10.64898/2026.02.27.708546. ABSTRACT Extrachromosomal DNA (ecDNA) is a major driver of oncogene amplification, tumour heterogeneity and poor clinical outcomes [1-3], yet its detection relies on specialised genomic assays that are not integrated into routine diagnostics. Here, we show that ecDNA status can be inferred directly from standard haematoxylin and eosin-stained whole-slide pathology images. We develop an end-to-end, weakly supervised deep learning framework that aggregates thousands of high-magnification patches per slide with slide-level augmentation and interpretable attention. Across twelve cancer types from The Cancer Genome Atlas, the approach identifies tumours with genomic amplifications and, critically, distinguishes ecDNA-amplified from chromosomally amplified or non-amplified tumours, with the strongest signal in glioblastoma. Attention maps localise regions enriched for nuclei with altered chromatin intensity and texture, and predicted ecDNA status recapitulates its adverse association with survival. These results indicate that ecDNA amplifications leave reproducible histomorphologic foot-prints detectable by routine pathology, enabling scalable screening to prioritise tumours for confirmatory molecular testing. PMID:41847039 | PMC:PMC12991143 | DOI:10.64898/2026.02.27.708546

Genet Med. 2026 Jan;28(1):101618. doi: 10.1016/j.gim.2025.101618. Epub 2025 Oct 24. ABSTRACT PURPOSE: For decades, the selection of disorders included in newborn screening (NBS) programs has been guided by principles published by Wilson and Jungner in 1968. As research explores the expansion of conditions included in NBS through genomic sequencing, there is a critical need for updated recommendations to address the opportunities and complexities of genomic data. METHODS: The International Consortium on Newborn Sequencing includes leaders from over 16 research projects investigating genomic NBS across the United Kingdom, Europe, United States, and Oceania. Consortium members were invited to participate in a modified Delphi study, aggregating opinion on the selection of conditions for genomic NBS through 3 rounds of online questionnaires, with feedback provided to participants between rounds. RESULTS: In round 1, 94 participants completed the questionnaire, and 10 of 43 statements reached consensus. In round 2, 81 participants completed the questionnaire, and 14 of 27 statements reached consensus. In round 3, 68 participants completed the questionnaire, and all 10 statements reached 72% or more consensus. CONCLUSION: The 10 consensus recommendations developed in this study can guide future research and public health programs performing genomic NBS. This process also identified key areas of participant discordance, highlighting important topics for future research. PMID:41765866 | PMC:PMC12950953 | DOI:10.1016/j.gim.2025.101618

Am J Hum Genet. 2026 Jan 15:S0002-9297(25)00482-3. doi: 10.1016/j.ajhg.2025.12.011. Online ahead of print. ABSTRACT ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2. We expand the clinical phenotypic descriptions of ASTN1-related NDDs, which range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficient hyperactivity disorder (ADHD), and epilepsy. Other recurrent abnormalities include dysmorphic facial features, hypotonia, spasticity, and ataxia. Additionally, we add to the neuroradiographic phenotype of this condition, which can be normal, mildly dysmorphic (a thin corpus callosum and cerebellar dysgenesis), or severely dysmorphic (polymicrogyria and lissencephaly). Remarkably, three genetic models of multilocus pathogenic variation (MPV), including tri-allelic, double heterozygous, and double homozygous due to distributive absence of heterozygosity (AOH), were observed. This ASTN1 allelic series characterizes the consequences of perturbations in radial-glia-guided neuronal migration in humans, the phenotypic spectrum of ASTN1-related NDDs, and the contribution of MPV to the genetic basis of NDDs. PMID:41544630 | DOI:10.1016/j.ajhg.2025.12.011

Crit Care. 2025 Dec 22. doi: 10.1186/s13054-025-05758-0. Online ahead of print. ABSTRACT PURPOSE: Humoral immunity proteins-immunoglobulins, complement proteins, and antimicrobial peptides-have key antimicrobial and immunomodulatory functions in sepsis. We hypothesised that their circulating levels are lower in non-survivors, potentially resulting in impaired bacterial clearance and persistent or recurrent infections. METHODS: We performed a systematic review and meta-analysis evaluating differences in humoral immunity proteins between survivors and non-survivors in adult patients with sepsis. PubMed and Embase were searched without date restrictions. Random-effects meta-analyses were used to estimate pooled standardised mean differences (SMD) with 95% confidence intervals (CI). Sensitivity analyses included data from the MIMIC-IV ICU database, and further supplemented by three proteomic studies. RESULTS: Thirty-six studies including 6,330 patients were analysed. Thirteen reported on immunoglobulins, 17 on complement proteins, and 7 on the antimicrobial peptide heparin-binding protein (HBP). Survivors had significantly higher levels of complement proteins C3 (SMD 0.53 [0.07-0.99]) and C4 (SMD 0.51 [0.09-0.94]) compared to non-survivors. Conversely, C4a (SMD – 1.17 [-1.77 to – 0.56]) and IgA (SMD – 0.21 [-0.39 to – 0.03]) were significantly lower in survivors. No differences were found for IgG (SMD 0.00 [-0.18 to 0.18]), IgM (SMD – 0.02 [-0.13 to 0.08]), C5, C5a, or HBP. Sensitivity analyses using MIMIC-IV (n = 2,452) and proteomic datasets supported these findings. Proteomic data revealed early depletion of classical complement components (C3, C4B) and regulatory proteins in non-survivors. CONCLUSION: Sepsis non-survivors exhibit lower C3 and C4 levels and higher C4a, consistent with complement activation and/or depletion. Complement proteins may serve as potential biomarkers and therapeutic targets in sepsis. PMID:41430733 | DOI:10.1186/s13054-025-05758-0

Nat Commun. 2025 Dec 20. doi: 10.1038/s41467-025-67614-7. Online ahead of print. ABSTRACT Extrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA’s spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression. PMID:41422275 | DOI:10.1038/s41467-025-67614-7

Nat Commun. 2025 Dec 10. doi: 10.1038/s41467-025-67257-8. Online ahead of print. ABSTRACT Estrogen receptor-positive breast cancer remains a leading cause of cancer-related death in women, with mortality largely driven by late recurrence of treatment-resistant disease. Loss of MLH1 promotes resistance to estrogen-targeting therapies by uncoupling cell cycle progression from estrogen regulation. Here, we show that even when MLH1 is abundantly expressed, aberrant cytoplasmic localization in a subset of tumor cells drives endocrine therapy resistance by enabling estrogen-independent growth. This resistance arises from failure to undergo robust cell cycle arrest in response to endocrine therapy, creating acute dependency on CDK4/6 activity. Consequently, CDK4/6 inhibitors induce strong regression in cells with cytoplasmic MLH1 compared to cells with nuclear MLH1. As cytoplasmic localization occurs in ~11% of ER+ patients, it represents a contributor to MLH1 dysregulation. Incorporating cytoplasmic MLH1 localization into diagnostics could guide the use of CDK4/6 inhibitors in this hard-to-treat subset. PMID:41372237 | DOI:10.1038/s41467-025-67257-8

Cell. 2025 Dec 4:S0092-8674(25)01310-8. doi: 10.1016/j.cell.2025.11.014. Online ahead of print. ABSTRACT Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4^R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease. PMID:41349546 | DOI:10.1016/j.cell.2025.11.014