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Results for “genotype-phenotype correlation”

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PubMed2025

Identification of intragenic variants in pediatric patients with intellectual disability in Peru.

BACKGROUND: Intellectual disability in Latin America can reach a frequency of 12% of the population, these may include nutritional deficiencies, exposure to toxic or infectious agents, and the lack of universal neonatal screening programs. In 90% of patients with intellectual disability, the etiology can be attributed to variants in the genome. OBJECTIVE: to determine intragenic variants in patients with intellectual disability between 5 and 18 years old at Instituto Nacional de Salud del Niño. METHODS: It is a descriptive cross-sectional study with convenience sampling. A total of 124 children diagnosed with intellectual disability were selected based on psychological test results and availability for whole exome sequencing. In addition, a chromosomal analysis of 6.55 M was performed on ten patients with a negative result in sequencing. Relative and absolute frequencies and measures of central tendency and dispersion were determined according to their nature. In addition, multiple linear regression and Poisson regression were used to determine the association between some clinical characteristics and the probability of occurrence in patients with positive results. RESULTS: The median age of the patients was 6.3 (IQR = 5.95), males accounted for 57.3%, and 91.9% of the cases had mild intellectual disability. Exome sequencing determined the etiology in 30.6% of patients with intellectual disability, of which 52.6% were autosomal dominant inheritance. The most frequent genes found were MECP2, STXBP1 and LAMA2. A broad genotype-phenotype correlation was identified, highlighting the genetic heterogeneity of intellectual disability in this population. The presence of dermatologic lesions, dystonia, peripheral neurological disorders, and fourth finger flexion limitation were observed more frequently in patients with intellectual disability with "positive results". CONCLUSIONS: This study shows that one-third of patients with intellectual disability exhibit intragenic variants, highlighting the importance of genetic analysis for accurate diagnosis. The identification of genes such as MECP2, STXBP1, and LAMA2 underscores the genetic heterogeneity of intellectual disability in the studied population. These findings emphasize the need for genetic testing in clinical management and the implementation of early detection programs in Peru.

Humans↗

PubMed2025

Exploring the c.406 C > T variant in TNNI3 gene: pathogenic insights into restrictive cardiomyopathy.

BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiac disorder characterized by diastolic dysfunction and myocardial stiffness, frequently associated with genetic variants. We aimed to explore the genetic basis of RCM in a diagnosed patient through comprehensive genetic analysis. METHODS: Whole exome sequencing (WES) was conducted on the proband, followed by Sanger sequencing for variant confirmation and familial segregation analysis. In silico tools and structural protein modeling were employed to assess the functional impact of the identified variant. RESULTS: The c.406 C > T variant, classified as likely pathogenic, results in a truncated TNNI3 protein. Bioinformatics analysis highlighted significant structural disruptions, likely impairing sarcomere function. The patient presented with growth retardation, progressive dyspnea, and echocardiographic findings consistent with RCM. Both parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern. The homozygosity of the novel variant identified in this study is a critical factor in the genotype-phenotype correlation observed in this case. CONCLUSION: This study identified the novel c.406 C > T variant in TNNI3 as a potential pathogenic driver of RCM, emphasizing the critical role of genetic evaluations in early diagnosis and management of inherited cardiomyopathies. Further studies are warranted to explore therapeutic interventions targeting TNNI3-related pathologies.

Humans↗

PubMed2026

Familial short stature: genetic architecture, risk stratification, and precision management.

BACKGROUND: Familial short stature (FSS) has traditionally been considered a benign growth pattern characterized by short stature clustering within families and has often been regarded as a normal variant of growth. However, recent advances in genomic technologies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants, particularly in genes involved in growth plate development and skeletal growth. These findings challenge the traditional phenotype-based understanding of FSS and support an etiology-oriented diagnostic framework. OBJECTIVE: To summarize current knowledge regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and evaluate available evidence regarding treatment outcomes across different genetic etiologies. METHODS: A literature search was performed in PubMed, Embase, and Web of Science from inception to May 2026, using keywords including "familial short stature," "familial idiopathic short stature," "genetic testing," "ACAN," "SHOX," and "NPR2". Relevant original studies and review articles addressing genotype-phenotype correlations, diagnostic yield of genetic testing, or responses to recombinant human growth hormone (rhGH) therapy were considered. RESULTS: Emerging evidence indicates that monogenic variants can be identified in a subset of children with an FSS phenotype, especially among those with more severe short stature and autosomal dominant inheritance patterns. Variants affecting growth plate biology represent some of the most frequently reported genetic causes of FSS, with ACAN, SHOX, and NPR2 being the most frequently implicated genes. Existing clinical frameworks based on parental height patterns and inheritance characteristics may help stratify patients with FSS according to the likelihood of monogenic etiology and guide selection of individuals who may benefit from genetic testing. Available evidence suggests that rhGH therapy may improve growth outcomes in several monogenic forms of FSS, although treatment responses vary according to genetic etiology. CONCLUSIONS: FSS should be regarded as a heterogeneous clinical phenotype rather than a single diagnostic entity. Integration of existing clinical risk stratification approaches with molecular diagnosis may enable more precise identification of underlying genetic causes and facilitate individualized therapeutic decision-making. Future advances in FSS management will likely depend on precision medicine approaches linking phenotype, genotype, and treatment response.

Humans↗

PubMed2026

Expanding the Genomic Spectrum of NHLRC2-Associated FINCA Disease: Integrated Bioinformatic Characterization of a Novel Deep Intronic Variant Predicted to Activate a Pseudoexon.

NHLRC2-associated FINCA disease is an ultra-rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in NHLRC2. Its mutational spectrum and genotype-phenotype correlations remain incompletely defined, and the contribution of non-coding variants is poorly understood. Here, we report a male infant with a severe FINCA-like phenotype, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months. Whole-genome sequencing identified a compound heterozygous NHLRC2 genotype comprising the previously reported pathogenic missense variant c.442G>T (p.Asp148Tyr) and a novel deep intronic variant, c.331+6863A>G. Segregation analysis confirmed inheritance from different parents. Integrated genomic and splicing analysis predicted that c.331+6863A>G creates a strong cryptic donor splice site and supports pseudoexon inclusion. Reconstruction of the predicted aberrant transcript indicated premature termination and potential susceptibility to nonsense-mediated mRNA decay. To our knowledge, this is the first reported deep intronic NHLRC2 variant predicted to activate pseudoexon inclusion. Although experimental validation was unavailable, convergent clinical, segregation, population, and computational evidence supports c.331+6863A>G as the most plausible second disease-associated allele. This case expands the genomic spectrum of NHLRC2-associated FINCA disease and highlights the diagnostic value of phenotype-driven whole-genome sequencing.

Humans↗

PubMed1992

[Retinitis pigmentosa. Clinical findings, results of molecular genetic techniques and research perspectives].

In recent years, research efforts in the basic and clinical sciences have yielded numerous new findings. The review given here outlines clinical findings, research results, and perspectives on the origin of hereditary retinal degeneration as far as molecular genetics, biochemistry, morphology, and clinical research are concerned: genotype-phenotype correlation, electroretinography, color perimetry, blue cone function, exogenous factors, refraction problems, fat metabolism, immunological aspects, retinal transplantation, and phenocopies of retinitis pigmentosa and related syndromes. The consequences for ophthalmological practice are pointed out and comprehensive, improved diagnostic procedures are recommended, using a checklist proposed here (see appendix).

Adult↗

PubMed1992

Short stature in a girl with a terminal Xp deletion distal to DXYS15: localisation of a growth gene(s) in the pseudoautosomal region.

This report describes a Japanese girl with short stature and a rearranged X chromosome. Her height remained below the 3rd centile growth curve for Japanese girls, and her predicted adult height (148.5 cm) was below her target height (163 cm) and target range (155 to 171 cm). Cytogenetic studies showed that the rearranged X chromosome was formed by a breakage at q26 and a transfer of the Xq fragment onto the tip of Xp. The abnormal X was always late replicating. No mosaicism was detected. Molecular analysis showed an Xp terminal deletion distal to DXYS15. Biochemical and radiological studies for short stature disclosed no abnormality. On the basis of height analysis of previous reports and a genotype-phenotype correlation of this patient, we propose that a growth gene(s) is present in the distal part of the pseudoautosomal region.

Blotting, Southern↗

PubMed2025

Spectrum of genetic variants associated with maple syrup urine disease in the Middle East, North Africa, and Türkiye (MENAT): a systematic review.

BACKGROUND: Maple syrup urine disease (MSUD) is a hereditary metabolic disorder caused by a deficiency in the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. The Middle East and North Africa, and Türkiye (MENAT) region has witnessed a significant rise in the prevalence of MSUD due to high rates of consanguinity. Despite numerous genetic association studies, the complex relationships between genotype and phenotype in MSUD remain elusive. AIM: This study aimed to systematically review the variants significantly associated with MSUD in the MENAT region. METHODS: We systematically searched four literature databases (PubMed, Scopus, Web of Science, and Science Direct) from inception until December 2023 to gather all reported genetic data pertaining to MSUD in the MENAT region. Quality assessment and data extraction were diligently performed by a team of six investigators. RESULTS: A total of 16 studies, involving patients, were included in this systematic review. Among them, 211 patients presented with 105 variants located within genes known to be associated with MSUD. The majority of the identified MSUD variants were found in BCKDHA (38%), followed by BCKDHB (38%), DBT (23%), and PPM1K (1%). Notably, 77% of the captured variants were unique to the MENAT region. CONCLUSION: Our systematic review reveals a distinctive genetic and clinical susceptibility profile of MSUD among individuals from the MENAT region. These findings highlight the importance of understanding the specific genetic landscape of MSUD in this population. Further research is warranted to elucidate the complex genotype-phenotype relationships in MSUD in the MENAT region.

Humans↗

PubMed2026

Two Bacillus PGPB Strains in Wheat and Soybean: Wheat Growth Promotion Without Detectable Rhizosphere Microbiome Restructuring.

Plant growth-promoting bacteria (PGPB) are increasingly deployed as biofertilizers, yet the link between an inoculant's genomic potential and its realized effect on the plant is rarely assessed within an integrative framework that jointly captures the rhizosphere microbiome, plant phenotype, and strain genome. Two Bacillus strains-B. halotolerans 1453 and B. pumilus 630-were applied to wheat and soybean in a factorial pot experiment (2 strains × 2 application methods × 3 frequencies + control, 3-4 replicates). Rhizosphere samples (n = 67 after filtering) were profiled by 16S rRNA sequencing with PICRUSt2 functional prediction and compositional validation (Aitchison PERMANOVA, ALDEx2, ANCOM-BC2). The PGPB gene repertoire was characterized by genome mining (481 marker genes, 14 categories). Wheat phenotype (six traits) and soybean height were analyzed with models appropriate for count data (Negative Binomial and binomial GLMs) for treatment-vs.-control comparisons, and with factorial ANOVA for decomposition into main effects and interactions. Crop identity was the dominant factor shaping both microbiome structure and function (PERMANOVA R2 = 14.7% taxonomically and R2 = 7.8% functionally, both p < 0.001), with biologically meaningful taxonomic differences between wheat and soybean; strain, application count and method had no significant effect on community composition (R2 < 4% each), and co-occurrence networks showed no reliable differences between crops once read depth and sample size were controlled for. Despite this neutrality at the microbiome level, inoculation significantly increased wheat spike count (NB-GLM, all 12 treatments vs. control, padj 0.0002-0.031), ear weight, and stem count, with application count the strongest source of variability and a pronounced strain × application count. Strain 1453 outperformed 630 in spike count (+23.1%, p = 0.012) and ear weight (+20.4%, p = 0.023); we hypothesize that this may be related to its more complete DNRA pathway (narGHI + nirB-nirD) and biocontrol genes (bacE, srfAA). Strain 630 produced a less pronounced effect than strain 1453 but was subject to smaller fluctuations across replicates (CV ≈ 16-21% vs. ≈24-26% for 1453), which may reflect better resilience to environmental fluctuations, possibly due to its confirmed rsbV/rsbW stress-tolerance regulon. Rhizosphere microbiome composition differed clearly by crop (wheat vs. soybean) but showed no detectable response to strain, application method, or application count. Despite this lack of a microbiome signal, inoculation significantly increased wheat spike count and ear weight, with the magnitude and stability of this effect differing by strain. We hypothesize that this strain-dependent difference relates to underlying genomic differences-particularly in nitrogen metabolism (DNRA pathway) and stress-tolerance genes-though this link has not been tested directly and remains a hypothesis for future work.

Triticum↗

PubMed2026

Molecular diagnosis of spinal muscular atrophy: Experience in a pediatric hospital in Argentina.

Introduction. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by the loss of the SMN1 gene, with a variable clinical spectrum determined primarily by the number of copies of the SMN2 gene. The development of new therapies underscores the importance of early molecular diagnosis and genotype-phenotype characterization. Objective. To describe 27 years of experience in the molecular diagnosis of SMA at a pediatric referral hospital in Argentina and to evaluate the correlation between SMN2 copy number and the SMA types.Population and methods. A retrospective descriptive study was conducted on 1060 pediatric patients with clinically suspected SMA who were evaluated between 1997 and 2024. Molecular diagnosis was performed using PCR-RFLP and, since 2012, MLPA to determine SMN1 and SMN2 copy number. Genotype-phenotype correlation was evaluated in 260 patients with complete clinical characterization. Results. The diagnosis was confirmed in 513 patients. A homozygous deletion of the SMN1 gene was detected in 99.6% of unrelated cases. The positivity rate increased over time. A significant correlation was observed between the number of SMN2 copies and the type of SMA, with milder phenotypes associated with a higher number of copies. Conclusion. Molecular diagnosis of SMA enabled accurate and timely characterization of patients, avoiding invasive procedures and optimizing therapeutic decision-making. Genotype-phenotype correlation is a fundamental tool for prognosis and clinical management, highlighting the importance of an interdisciplinary approach.

Argentina↗

PubMed2026

Robust replication of associations across patient-mediated and provider-sourced EHR data in the All of Us research program.

The All of Us Research Program is assembling a nationwide cohort with electronic health record (EHR) resources through two complementary pathways: healthcare provider organization (HPO)-sourced EHRs and patient-mediated EHR (PME) contributed through patient portal linkages. The comparative research utility of these two data sources has not been systematically evaluated. Here, we compared PME and HPO EHRs with respect to disease prevalence, phenotype-phenotype associations, and replication of established genotype-phenotype associations using data from 19,703 PME and 373,887 HPO participants. We benchmarked disease prevalence against national estimates, conducted phenome-wide association studies for 10 commonly studied diseases, and tested replication of more than 5000 established genotype-phenotype associations across multiple ancestral groups. Disease prevalence was consistently lower in PME than in HPO, although prevalence of most diseases in both cohorts exceeded national estimates. Both data sources reproduced known phenotype-phenotype associations and showed moderate-to-strong concordance in effect sizes across the phenome. The overall genotype-phenotype replication rate was 49.1% (5399/10,999) in HPO and 5.9% (381/6482) in PME across ancestral groups, with effect sizes strongly correlated among well-powered associations (R = 0.84, P < 0.001). To disentangle the impact of sample size from data quality, we performed 1:1 propensity score matching. After matching, the replication gap in genotype-phenotype associations narrowed from 8.3-fold to 1.3-fold, with equivalent replication rates among adequately powered associations and strongly concordant effect sizes; comorbidity patterns were also consistent across all 10 diseases tested. These findings demonstrate that both data sources are valuable for clinical and genomic research and can inform other cohorts integrating provider-derived and patient-mediated EHRs.

Computational biology and bioinformatics↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Phylogeographic epidemiology of Dabie bandavirus in East Asia: divergent transmission networks and genotype‑linked clinical severity.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus (SFTSV), exhibits geographically decoupled incidence and fatality patterns across East Asia. We aimed to elucidate the distinct ecological drivers and phylogeographic dynamics underlying this inland-coastal epidemiological divergence. METHODS: Integrating 1820 high-quality global genomes of SFTSV with well-characterized clinical cohorts (936 patients) and nationwide surveillance data (27,457 cases) from China, we constructed a comprehensive analytical framework. Ecological modeling, Bayesian phylogeography, and genotype-phenotype association analyses were employed to trace the evolutionary trajectories and clinical implications of the virus. RESULTS: A pronounced "inland-high-incidence vs. coastal-high-fatality" pattern of SFTS was identified. The incidence of SFTS exhibited divergent sensitivities to meteorological factors; inland transmission was sensitive to thermal fluctuations, whereas coastal dynamics were constrained by a sunshine threshold (> 200 h/month). In contrast, spatial divergence in clinical severity correlated with the distribution of regional viral genetic structures. Inland regions mainly co-circulated genotypes A, C, and D, while coastal regions were dominated by genotype B. Zhejiang province was identified as a genetic hub with significantly higher recombination frequencies than inland regions (11.0% vs. 3.5%, P < 0.001). Bayesian phylogeographic inference indicated frequent lineage exchange of Zhejiang province in China with the Republic of Korea and Japan. Clinically, genotypes B and D were associated with elevated mortality in coastal and inland regions, respectively, suggesting that the severe coastal phenotype is shaped by its genotype B-dominated structure. Additionally, the RdRp-N828S mutation emerged as a robust molecular correlate of fatal outcomes, warranting further functional validation. CONCLUSIONS: Divergent meteorological factors and plausible maritime transmission networks may underlie the geographically decoupled epidemiology of SFTS. These findings highlight that risk assessment must extend beyond incidence alone and provide a phylogeographically informed framework for targeted surveillance and genotype-specific interventions in high-risk hotspots.

Humans↗

PubMed2024

Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast.

Gene expression varies between individuals and corresponds to a key step linking genotypes to phenotypes. However, our knowledge regarding the species-wide genetic control of protein abundance, including its dependency on transcript levels, is very limited. Here, we have determined quantitative proteomes of a large population of 942 diverse natural Saccharomyces cerevisiae yeast isolates. We found that mRNA and protein abundances are weakly correlated at the population gene level. While the protein coexpression network recapitulates major biological functions, differential expression patterns reveal proteomic signatures related to specific populations. Comprehensive genetic association analyses highlight that genetic variants associated with variation in protein (pQTL) and transcript (eQTL) levels poorly overlap (3%). Our results demonstrate that transcriptome and proteome are governed by distinct genetic bases, likely explained by protein turnover. It also highlights the importance of integrating these different levels of gene expression to better understand the genotype-phenotype relationship.

Saccharomyces cerevisiae↗

PubMed2025

Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.

Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.

Breast Neoplasms↗

PubMed2026

Twenty-Three Years of Surveillance in Chinese Avian Pasteurella multocida Reveals Declining Antimicrobial Resistance but Increasing Therapeutic Challenges.

Pasteurella multocida (Pm) is an important veterinary and zoonotic pathogen that causes significant economic losses in poultry production. However, long-term surveillance studies integrating antimicrobial resistance (AMR), biocide tolerance, and genomic epidemiology of Pm remain scarce. In this study, we investigated the antimicrobial susceptibility, biocide tolerance, and the phenotypic associations of 136 avian Pm isolates collected from six provinces in China between 2002 and 2024. Whole-genome sequencing was performed to characterize population structure, identify antimicrobial resistance genes (ARGs), and assess genotype-phenotype concordance. The A:L1:ST129 lineage remained the predominant clone throughout the 23-year surveillance period, with a high prevalence of AMR-associated traits observed within this lineage. Although resistance to several commonly used antimicrobial classes declined significantly after 2021, florfenicol resistance continued to increase, suggesting an emerging challenge for the clinical management of pasteurellosis. While the isolates generally exhibited low tolerance to the four representative biocides tested, phenotypic correlations were observed between AMR profiles and biocide tolerance patterns. Furthermore, substantial phenotype-genotype discordance was observed, indicating that the presence of ARGs alone may not be sufficient to accurately predict antimicrobial susceptibility. Overall, this study provides a longitudinal assessment of long-term AMR trends, biocide tolerance, and genomic epidemiology of avian Pm in China, offering epidemiological evidence for monitoring AMR trends and improving antimicrobial management strategies in poultry production.

Animals↗

PubMed2026

Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.

OBJECTIVES: VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. METHODS: We conducted longitudinal deep phenotyping, including whole-blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. RESULTS: Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes upregulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, FDR < 0.05) and was upregulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 upregulation, all following the same graded pattern, recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathological features, including RNASE1 upregulation. CONCLUSIONS: Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.

Journal Article↗

PubMed2026

Genetic and epigenetic determinants of cytochrome P450 activity in psychopharmacology: from pharmacogenetics to functional pharmacogenomics.

Classical pharmacogenetics has explained interindividual variability in psychotropic drug response primarily through inherited polymorphisms in cytochrome P450 enzymes. This framework successfully identified extreme metabolizer phenotypes and informed genotype-guided dosing recommendations. However, genotype-based predictions frequently correlate more strongly with pharmacokinetic parameters than with clinical outcomes. Patients sharing similar CYP genotypes often exhibit divergent therapeutic trajectories, while metabolic phenotypes may change during treatment without corresponding alterations in DNA sequence. These observations suggest the existence of a genotype-phenotype gap mediated by regulatory processes not captured by genotyping alone. Evidence from epigenetic regulation, environmental modulation of pharmacogene expression, and phenoconversion indicates that metabolic capacity is better understood as a dynamic functional state rather than a fixed inherited trait. This review examines the role of these mechanisms in psychiatric pharmacotherapy and explores the implications of shifting the predictive focus of precision medicine from static genotype to functional state.

Humans↗

PubMed2026

Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.

Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.

Humans↗