2025
Evaluating pathogenicity of TPM1 variants of unknown significance using in-silico and in-vitro models
Halder S, Bellitto J, Rynkiewicz M, Cheung F, Liu D, Firlar I, Bongiorno A, Barry M, Sewanan L, Moore J, Lehman W, Campbell S. Evaluating pathogenicity of TPM1 variants of unknown significance using in-silico and in-vitro models. The Journal Of Precision Medicine Health And Disease 2025, 2: 100008. DOI: 10.1016/j.premed.2025.100008.Peer-Reviewed Original ResearchIn vitro motilityFilament motilityContext of cardiomyopathyVariant classificationGenetic screeningTwitch contraction forceComputational pipelineMyosin activityEvaluate pathogenicityDiversity changesFunctional studiesIn silicoTropomyosinTPM1VUSMotilityInherited cardiomyopathyCa2+ sensitivityVariantsIn vitro modelIn vitro dataReduced abilityIPSC-derived cardiomyocytesLow Ca2+Ca2+The Psychiatric Genomics Consortium: discoveries and directions
Agrawal A, Bulik C, Abebe D, Andreassen O, Atkinson E, Choi K, Corvin A, Davies H, Davis L, Docherty A, Edenberg H, Franke B, Gelernter J, Giusti-Rodríguez P, Hettema J, Hjerling-Leffler J, Huang H, Johnson E, Lewis C, Lu Y, Lynall M, Martin J, McIntosh A, Montalvo-Ortiz J, Mullins N, Nievergelt C, O'Connell K, O'Donovan M, Okewole A, Peterson R, Posthuma D, Sebat J, Smoller J, Sud R, Viswanath B, Walters J, Won H, Wray N, Sullivan P, Consortium T. The Psychiatric Genomics Consortium: discoveries and directions. The Lancet Psychiatry 2025 PMID: 40582370, DOI: 10.1016/s2215-0366(25)00124-5.Peer-Reviewed Original ResearchPsychiatric Genomics ConsortiumGenome-wide association studiesFunctional genomics dataRare genetic variationPsychiatric disordersGenomic dataAssociation studiesGenetic variationGenomic discoveriesNeurodevelopmental conditionsPolygenic riskPolygenic scoresGenomics ConsortiumGenetic causeRare variantsRare variationImplementation processGlobal morbidityFunctional attributesPriority areasIntegrated findingsMultiple psychiatric disordersNext phaseVariantsDiscoveryProtocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes
Gauthier L, Wang Z, Ng K, Huang S, Mao Y, Lek M, Ma K. Protocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes. STAR Protocols 2025, 6: 103909. PMID: 40540392, DOI: 10.1016/j.xpro.2025.103909.Peer-Reviewed Original ResearchDisease-related genesDisease-causing genetic variantsFluorescence-based cell sortingNext-generation sequencingFunctional assaysDisease genesAllelic seriesSaturation mutagenesisGenetic variantsGenesFunctional impactCell sortingHigh-throughputVariantsDisease fieldAssayMutagenesisSequenceCellsNucleofectionSortingLinear epidermal nevus associated with a novel mosaic heterozygous PTPN11 variant
Jiang X, Chen T, Hu R, Mortlock R, Ko C, Choate K. Linear epidermal nevus associated with a novel mosaic heterozygous PTPN11 variant. British Journal Of Dermatology 2025, ljaf210. PMID: 40442926, DOI: 10.1093/bjd/ljaf210.Peer-Reviewed Original ResearchUnveiling the shared etiology between gastrointestinal disorders and valvular heart diseases through a genome-wide pleiotropy study
Xu J, Liu Z, Wu L, Pei F, Jiang H, Cheng C, Yang W, Yuan J, Polimanti R, Yang Y. Unveiling the shared etiology between gastrointestinal disorders and valvular heart diseases through a genome-wide pleiotropy study. Npj Cardiovascular Health 2025, 2: 17. DOI: 10.1038/s44325-025-00054-w.Peer-Reviewed Original ResearchLinkage disequilibrium score regressionGenetic correlationsPleiotropic analysisPleiotropy analysisGut microbiotaGenetic pathwaysMicrobial influenceScore regressionPleiotropic effectsGenetic linkPathwayHeart diseaseButyricicoccusMicrobiotaGenesGutComposite null hypothesisVariantsGastrointestinal disordersCausal effectsLinkageDiseaseIBDAssociation of clinical manifestations and immune alterations with genetic variants of uncertain significance in patients concerned for inborn errors of immunity
Novotny S, Yoo N, Chen J, Granoth M, Kohli-Pamnani A, Hsu F, Rodenas M, Steele R, Kaman K, Soffer G, Price C, Kuster J, Kang I, Osmani L, Shin J. Association of clinical manifestations and immune alterations with genetic variants of uncertain significance in patients concerned for inborn errors of immunity. Clinical Immunology 2025, 277: 110513. PMID: 40354868, DOI: 10.1016/j.clim.2025.110513.Peer-Reviewed Original ResearchInborn errors of immunityErrors of immunityGenetic variantsInborn errorsAssociation of clinical manifestationsGene clusterGene functionStudy evaluated associationsImmune alterationsDiagnostic challengeClinical manifestationsImmunological profileGenetic testingVUSGenesImmunological characteristicsImmune functionLaboratory dataImmunityVariantsAssociationPatientsEarly Release - Large-Scale Genomic Analysis of SARS-CoV-2 Omicron BA.5 Emergence, United States - Volume 31, Supplement—May 2025 - Emerging Infectious Diseases journal - CDC
Pham K, Chaguza C, Lopes R, Cohen T, Taylor-Salmon E, Wilkinson M, Katebi V, Grubaugh N, Hill V. Early Release - Large-Scale Genomic Analysis of SARS-CoV-2 Omicron BA.5 Emergence, United States - Volume 31, Supplement—May 2025 - Emerging Infectious Diseases journal - CDC. Emerging Infectious Diseases 2025, 31: s45-s56. PMID: 40359081, PMCID: PMC12078544, DOI: 10.3201/eid3113.240981.Peer-Reviewed Original ResearchCell-Free Protein Synthesis as a Method to Rapidly Screen Machine Learning-Generated Protease Variants
Thornton E, Boyle J, Laohakunakorn N, Regan L. Cell-Free Protein Synthesis as a Method to Rapidly Screen Machine Learning-Generated Protease Variants. ACS Synthetic Biology 2025, 14: 1710-1718. PMID: 40304425, PMCID: PMC12090339, DOI: 10.1021/acssynbio.5c00062.Peer-Reviewed Original ResearchTrio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families
Merz L, Kolvenbach C, Wang C, Mertens N, Seltzsam S, Mansour B, Zheng B, Schneider S, Schierbaum L, Hölzel S, Salmanullah D, Pantel D, Kalkar G, Connaughton D, Mann N, Wu C, Kause F, Nakayama M, Dai R, Schneider R, Buerger F, Nicolas-Frank C, Yousef K, Lemberg K, Saida K, Yu S, Elmubarak I, Franken G, Lomjansook K, Braun A, Bauer S, Rodig N, Somers M, Traum A, Stein D, Daga A, Baum M, Daouk G, Awad H, Eid L, El Desoky S, Shalaby M, Kari J, Ooda S, Fathy H, Soliman N, Nabhan M, Abdelrahman S, Hilger A, Mane S, Ferguson M, Tasic V, Shril S, Hildebrandt F. Trio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families. Genetics In Medicine 2025, 27: 101432. PMID: 40223730, DOI: 10.1016/j.gim.2025.101432.Peer-Reviewed Original ResearchCandidate genesExome sequencingDisease genesPotential novel candidate genesCandidate disease genesTrio-based exome sequencingDe novo variantsTrio exome sequencingDisease etiologyPathogenesis of CAKUTPotential novel causeTrio familiesTrio analysisMonogenic genesGenesNovel causeCHD1LSOX13VariantsTriosSequenceCongenital anomaliesHeterogeneous malformationUrinary tractCAKUTThe interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease
Vilarinho S. The interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease. Nature Genetics 2025, 57: 775-776. PMID: 40169790, DOI: 10.1038/s41588-025-02151-z.Peer-Reviewed Original ResearchPlant graph-based pangenomics: techniques, applications, and challenges
Du Z, He J, Jiao W. Plant graph-based pangenomics: techniques, applications, and challenges. ABIOTECH 2025, 1-16. DOI: 10.1007/s42994-025-00206-7.Peer-Reviewed Original ResearchNovo-assembled genomeMolecular breeding of cropsDNA sequencing technologiesInvestigate population diversityAgronomically important genesBreeding of cropsPangenome graphsGenetic mapSmall variantsGenomic regionsGenetic diversityGraph pangenomeSequencing technologiesGenomic analysisPangenomic studiesGenomic studiesGenetic variationImportant genesMolecular breedingStructural variantsPangenomeGenomeCrop breedingPlantsVariantsCharacterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder
Abdallah S, Olfson E, Cappi C, Greenspun S, Zai G, Rosário M, Willsey A, Shavitt R, Miguel E, Kennedy J, Richter M, Fernandez T. Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder. Journal Of The American Academy Of Child & Adolescent Psychiatry 2025 PMID: 40122455, DOI: 10.1016/j.jaac.2025.03.014.Peer-Reviewed Original ResearchCopy-number variantsWhole-exome DNA sequencingEXome-Hidden Markov ModelDetect copy-number variantsSingle-nucleotide variantsGenetic factorsWhole-exome sequencingExamination of genesBiological systems analysisTrio familiesDNA sequencesMicroarray dataOCD riskBurden analysisBiological processesGenesSequenceVariantsObsessive-compulsive disorderPrimary analysisXHMMPediatric obsessive-compulsive disorderCompared to controlsFamilySilicoIdentification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities
Loesch D, Garg M, Matelska D, Vitsios D, Jiang X, Ritchie S, Sun B, Runz H, Whelan C, Holman R, Mentz R, Moura F, Wiviott S, Sabatine M, Udler M, Gause-Nilsson I, Petrovski S, Oscarsson J, Nag A, Paul D, Inouye M. Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities. Nature Communications 2025, 16: 2124. PMID: 40032831, PMCID: PMC11876343, DOI: 10.1038/s41467-025-56695-z.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersCardiovascular DiseasesComorbidityDiabetes Mellitus, Type 2Extracellular Matrix ProteinsFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansInsulin-Like Growth Factor Binding Protein 2MaleMiddle AgedMultifactorial InheritanceProteomicsRisk FactorsUnited KingdomConceptsPolygenic scoresNon-coding variantsEtiology of type 2 diabetesMolecular dataVariant effectsPathway enrichmentPlasma proteomic markersPotential therapeutic targetType 2 diabetesProteinDisease biologyPolygenic riskUK BiobankProteomic markersTherapeutic targetPathwayCirculating proteinsGenomeRisk of type 2 diabetesCardiometabolic scoreBiologyInteractive portalVariantsEnrichmentDiabetes comorbiditiesEmpowering genome-wide association studies via a visualizable test based on the regional association score
Jiang Y, Zhang H. Empowering genome-wide association studies via a visualizable test based on the regional association score. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2419721122. PMID: 39999171, PMCID: PMC11892588, DOI: 10.1073/pnas.2419721122.Peer-Reviewed Original ResearchModeling thoracic aortic genetic variants in the zebrafish: useful for predicting clinical pathogenicity?
Prendergast A, Sheppard M, Famulski J, Nicoli S, Mukherjee S, Sips P, Elefteriades J. Modeling thoracic aortic genetic variants in the zebrafish: useful for predicting clinical pathogenicity? Frontiers In Cardiovascular Medicine 2025, 12: 1480407. PMID: 40066353, PMCID: PMC11892108, DOI: 10.3389/fcvm.2025.1480407.Peer-Reviewed Original ResearchPathogenicity of VUSProportion of variantsMedical genetic testingCausal genesPathogenicity assessmentClinical pathogensTested pathogensGenetic variantsCausative genesTAAD casesGenesGenetic defectsGenetic testingThoracic aortic aneurysmHeritable genetic defectsImpact cardiovascular morbidityPathogensVUSAortic aneurysmCardiovascular morbidityVariantsZebrafishTAADClinical applicationEnhance patient careCharacterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants
Jawaid T, Elbarougy D, Lavu S, Buia G, Senum S, Olinger E, Yang H, McDonnell S, Bublitz J, Ma J, Audrézet M, Madsen C, Schauer R, Baker T, Gregory A, Orr S, Barroso-Gil M, Neatu R, Joli G, Dahl N, Kline T, Gillion V, Dahan K, Jouret F, Perrone R, Steinman T, Peters D, Gitomer B, Watnick T, Coto E, Chebib F, Hogan M, Olson J, Larson N, Ars E, Halbritter J, Demoulin N, Torres V, Sayer J, Gall E, Harris P. Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants. Journal Of The American Society Of Nephrology 2025, 36: 1056-1071. PMID: 39899384, PMCID: PMC12147961, DOI: 10.1681/asn.0000000613.Peer-Reviewed Original ResearchPathogenic variantsAutosomal dominant polycystic kidney diseaseAutosomal dominant polycystic kidney disease geneCystic kidneysKidney cystsPKD phenotypeSequence dataAutosomal dominant polycystic liver diseaseALG8ALG9Kidney phenotypeGenesDominant polycystic kidney diseaseInherited nephropathyAnalysis of individualsPathogenic changesPolycystic kidney diseasePKD1PhenotypeKidney diseaseMcbBMutationsVariantsLiver diseaseKidney failureInvestigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries
Wang L, Kranzler H, Gelernter J, Zhou H. Investigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries. Biological Psychiatry 2025, 98: 46-55. PMID: 39892688, PMCID: PMC12167164, DOI: 10.1016/j.biopsych.2025.01.020.Peer-Reviewed Original ResearchContribution of coding variantsGene-based collapsing testAlcohol use disorderAnalyzed whole-exome sequencing dataEuropean ancestryContribution of rare coding variantsRare loss-of-functionWhole-exome sequencing dataWhole-exome sequencing studiesRare coding variantsAfrican ancestryWhole-exome sequencingLoss-of-functionGenetic architectureSequence dataAllelic heterogeneityMissense variantsGenetic variantsAllele frequenciesRare variantsYale-PennStudy of alcohol use disorderUK BiobankUK Biobank cohortVariantsExploring Possible Drug-Resistant Variants of SARS-CoV‑2 Main Protease (Mpro) with Noncovalent Preclinical Candidate, Mpro61
Kenneson J, Papini C, Tang S, Huynh K, Zhang C, Jorgensen W, Anderson K. Exploring Possible Drug-Resistant Variants of SARS-CoV‑2 Main Protease (Mpro) with Noncovalent Preclinical Candidate, Mpro61. ACS Bio & Med Chem Au 2025, 5: 215-226. PMID: 39990941, PMCID: PMC11843330, DOI: 10.1021/acsbiomedchemau.4c00109.Peer-Reviewed Original ResearchDrug resistance mutationsViral passaging experimentsDrug-resistant clinical isolatesCOVID infectionDrug-resistant variantsSARS-CoV-2 MClinical isolatesPassage experimentsIncreased up to 10-foldClinical useSARS-CoV-2 main proteaseWild typePreclinical candidateDouble variantInhibitorsMutationsDrug developmentInfectionNirmatrelvirMain proteaseProlonged usageMedicinal chemistry modificationsVariantsTarget-based approachPatientsA Comprehensive Bioinformatics Approach to Analysis of Variants: Variant Calling, Annotation, and Prioritization
Koroglu M, Bilguvar K. A Comprehensive Bioinformatics Approach to Analysis of Variants: Variant Calling, Annotation, and Prioritization. Methods In Molecular Biology 2025, 2889: 207-233. PMID: 39745615, DOI: 10.1007/978-1-0716-4322-8_15.Peer-Reviewed Original ResearchConceptsGenomic dataHigh-throughput sequencing technologyGenomic data analysisField of genomicsNext-generation sequencingVariant callingNGS technologiesSequencing technologiesBioinformatics approachComprehensive computational approachSequenceComputational approachCancer researchGenomeTranscriptomeBioinformaticsNGSProteomicsNext-generationDNARNAEfficient sequenceAnnotationVariantsFragmentsCoupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits
Scherer N, Fässler D, Borisov O, Cheng Y, Schlosser P, Wuttke M, Haug S, Li Y, Telkämper F, Patil S, Meiselbach H, Wong C, Berger U, Sekula P, Hoppmann A, Schultheiss U, Mozaffari S, Xi Y, Graham R, Schmidts M, Köttgen M, Oefner P, Knauf F, Eckardt K, Grünert S, Estrada K, Thiele I, Hertel J, Köttgen A. Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. Nature Genetics 2025, 57: 193-205. PMID: 39747595, PMCID: PMC11735408, DOI: 10.1038/s41588-024-01965-7.Peer-Reviewed Original ResearchConceptsWhole-exome sequencing dataGene-metabolite associationsHuman traitsHuman metabolic reactionsSequence dataAllelic seriesGene functionExome sequencingFunctional variantsGenetic studiesInborn errors of metabolismHeterozygous variantsErrors of metabolismMusculoskeletal traitsMetabolic reactionsHuman heightUrine metabolitesHeterozygous stateSulfate reabsorptionInborn errorsTraitsAggregation testVariantsHuman metabolismMetabolomics
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