Cell Genomics

MotivationFanconi anemia (FA) is a rare disease mainly caused by biallelic pathogenic variants, including structural variants such as large deletions and insertions in FA genes. Currently, variant detection is based on short-read sequencing and probe-based approaches. However, determining the exact genomic breakpoint or achieving allelic discrimination remains challenging. Nanopore-based long-read sequencing enables a comprehensive detection of FA variants, but a unified bioinformatic analysis p...

Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part o...

Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface inte...

Tumour typing from whole-genome sequencing is increasingly accurate, yet molecular subtyping from somatic variants remains challenging because of tumour heterogeneity and inconsistent clinical annotations. Here, we present Mutation-Attention Dual-Task (MuAt2), a Transformer model that jointly classifies histological tumour types and subtypes directly from somatic single-nucleotide variants, indels and structural variants. MuAt2 leverages encoders pre-trained on 2,587 pan-cancer whole genomes, an...

BackgroundA coronary artery calcium (CAC) score of 0 is widely considered to indicate low short- to intermediate-term risk for coronary artery disease (CAD) and is frequently used to defer lipid-lowering therapy. However, a subset of individuals with CAC=0 still experience events, highlighting residual risk not captured by imaging alone. Polygenic risk scores (PRS) quantify lifelong inherited susceptibility, but conventional approaches rely on predefined ancestry labels despite human genetic div...

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential me...

Accurate classification of BRCA1 and BRCA2 variants is essential for cancer risk assessment and therapy selection, yet over one-third remain variants of uncertain significance (VUS). Here, using 120,660 real-world cancer genomic profiles with BRCA1 or BRCA2 variants from a >800,000-sample cohort, we develop machine learning models that predict pathogenicity using clinical and tumor-derived features, including a pan-cancer homologous recombination deficiency signature, co-mutated genes, zygosity,...

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([≤]130 mg/dL, n=...

BackgroundThe relationship between hip osteoarthritis (hip OA) and Alzheimers disease (AD) presents a critical paradox within the emerging "bone-brain axis": widespread phenotypic comorbidity sharply contradicts evolutionary theories of biological antagonism. This study integrates longitudinal and multi-omic analyses to determine whether this clinical overlap masks an underlying genetic neuroprotection. MethodsWe analyzed longitudinal phenotypic data from 261,767 UK Biobank participants using C...

RIG-I is a cytosolic immune receptor that provides the first line of defense by detecting viral RNA and triggering antiviral responses. Its physiological role in humans remains unclear, as no patients with complete RIG-I deficiency have yet been reported. We identified a critically ill COVID-19 patient with severe RIG-I deficiency caused by heterozygous RIG-I G731R, a novel dominant loss-of-function variant. The G731R mutation in helicase motif VI disrupts the arginine finger, impairing the ATPa...

BackgroundKlebsiella pneumoniae is a common cause of neonatal sepsis in Africa, and is frequently hospital acquired. We recently reported an outbreak of multidrug-resistant K. pneumoniae sepsis amongst neonates at a rural hospital in The Gambia, West Africa, involving 57 cases and case fatality of 60%. Here we undertook a retrospective pathogen genomic epidemiology study of clinical and environmental K. pneumoniae isolated during the outbreak, to identify the outbreak strain, refine the epidemic...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...

Understanding host susceptibility to Mycobacterium tuberculosis (Mtb) is critical for the development of new vaccines. Certain individuals "resist" becoming infected with Mtb despite intensive exposure; however, it is unknown whether there is a genetic basis for "resistance" to Mtb infection across populations. Here we conducted a genome-wide association study (GWAS) of resistance to Mtb infection by carefully characterizing exposure to TB patients among 4,058 close contacts in India, Brazil, an...

Anti-{beta}2-glycoprotein I (anti-{beta}2GPI) antibodies are central to the pathogenesis of antiphospholipid syndrome (APS), an autoimmune disease characterized by a strong predisposition to venous thromboembolism (VTE). In this study, we conducted a multi-ancestry genome-wide association study (GWAS) of quantitative total anti-{beta}2GPI levels in 5,969 participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) and identified a genome-wide significant association at the APOH locu...

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants wi...

Accurate polyp segmentation from colonoscopy images is critical for colorectal cancer prevention, yet the generalization of deep learning models under domain shift remains insufficiently explored. We propose Boundary-Explicit Guided Attention U-Net (BEGA-UNet), a boundary-aware segmentation architecture that introduces explicit edge modeling as a structural inductive bias to enhance both segmentation accuracy and cross-domain robustness. The framework integrates three components: an Edge-Guided ...

Study question: How is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answer: We present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known already: Glycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determi...

The use of semaglutide (SE), a glucagon-like peptide-1 receptor agonist (GLP-1RA) with glucose-lowering and weight-loss effects, has risen rapidly, particularly among women of reproductive age. While preclinical studies suggest benefits for ovarian function via the hypothalamic-pituitary-ovarian axis, its impact on the endometrial-embryo interface remains unclear. Here, we show that GLP-1R is dynamically expressed in fertile human endometrium, restricted to epithelial cells and markedly upregula...

BackgroundHypertension affects over 30% of adults and is the leading risk factor for cardiovascular disease. It often presents without obvious symptoms, meaning that, although effective therapies exist, hypertension remains widely undiagnosed and insufficiently treated. Genomics-based prediction methods have shown only modest benefits for these disorders, but proteomic markers have demonstrated potential for greater predictive and clinical value. MethodsWe applied a novel machine-learning based...

IntroductionGenome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFRcrea), which is affected by variation in muscle mass. Moreover, the genetic basis of the sexual dimorphism of chronic kidney disease is underexplored. MethodsWe performed a GWA meta-analysis for creatinine clearance (CrCl), a muscle mass-independent kidney function phenotype, in 58,976 individuals of European descent from the Lifelines Cohort Study. Res...