2023
Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease
Tambi R, Zehra B, Nandkishore S, Sharafat S, Kader F, Nassir N, Mohamed N, Ahmed A, Abdel Hameid R, Alasrawi S, Brueckner M, Kuebler W, Chung W, Alsheikh-Ali A, Di Donato R, Uddin M, Berdiev B. Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease. Physiological Genomics 2023, 55: 634-646. PMID: 37811720, PMCID: PMC11550899, DOI: 10.1152/physiolgenomics.00070.2023.Peer-Reviewed Original ResearchConceptsSingle-cell transcriptomesCHD genesRisk genesEndocardial cellsMultiple genesCell typesSingle-cell transcriptomicsPhenotypic heterogeneityDe novo variantsCongential heart diseaseSingle-cell reconstructionGenesReconstruction analysisNeonatal congenital anomaliesGene heterogeneityAnalysis identifiesTranscriptomeMissense variantsNovo variantsCongenital heart diseaseGenomicsHeterogenous expressionFunction variantsHeart diseaseGenetics guidelines
2022
Quantifying concordant genetic effects of de novo mutations on multiple disorders
Guo H, Hou L, Shi Y, Jin SC, Zeng X, Li B, Lifton R, Brueckner M, Zhao H, Lu Q. Quantifying concordant genetic effects of de novo mutations on multiple disorders. ELife 2022, 11: e75551. PMID: 35666111, PMCID: PMC9217133, DOI: 10.7554/elife.75551.Peer-Reviewed Original ResearchMutation spectrum of congenital heart disease in a consanguineous Turkish population
Dong W, Kaymakcalan H, Jin SC, Diab NS, Tanıdır C, Yalcin ASY, Ercan‐Sencicek A, Mane S, Gunel M, Lifton RP, Bilguvar K, Brueckner M. Mutation spectrum of congenital heart disease in a consanguineous Turkish population. Molecular Genetics & Genomic Medicine 2022, 10: e1944. PMID: 35481623, PMCID: PMC9184665, DOI: 10.1002/mgg3.1944.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingLaterality defectsUnique genetic architectureCongenital heart diseaseConsanguineous familyGenetic architectureCausal genesCHD genesGenome analysisHomozygous variantGenetic landscapeGenetic lesionsGenomic alterationsHeart diseaseConsanguineous populationFunction variantsRecessive variantsCHD probandsGenesType of CHDMutation spectrumStructural congenital heart diseaseVariantsCHD subjectsAdditional patients
2021
Molecular Genetics and Complex Inheritance of Congenital Heart Disease
Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, Kahle KT, Brueckner M, Jin SC. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes 2021, 12: 1020. PMID: 34209044, PMCID: PMC8307500, DOI: 10.3390/genes12071020.Peer-Reviewed Original ResearchConceptsHigh-throughput genomic technologiesHigh-throughput sequencingGenetic architectureCHD familyGenetic variationSophisticated analysis strategiesCilia genesComplex inheritancePathway genesDe novo mutationsGenomic technologiesCauses of CHDMolecular geneticsBiological pathwaysMolecular diagnosisNumber variationsVEGF pathway genesGenesChromatinMutationsNovo mutationsGenetic etiologyTransmitted mutationsGenetic explanationSequencing
2020
De novo damaging variants associated with congenital heart diseases contribute to the connectome
Ji W, Ferdman D, Copel J, Scheinost D, Shabanova V, Brueckner M, Khokha MK, Ment LR. De novo damaging variants associated with congenital heart diseases contribute to the connectome. Scientific Reports 2020, 10: 7046. PMID: 32341405, PMCID: PMC7184603, DOI: 10.1038/s41598-020-63928-2.Peer-Reviewed Original ResearchMeSH KeywordsConnectomeDNA HelicasesDNA-Binding ProteinsExomeFemaleHeart Defects, CongenitalHistone-Lysine N-MethyltransferaseHomeodomain ProteinsHumansMaleMi-2 Nucleosome Remodeling and Deacetylase ComplexMutationMutation, MissenseMyeloid-Lymphoid Leukemia ProteinNerve Tissue ProteinsProtein Tyrosine Phosphatase, Non-Receptor Type 11Receptor, Notch1ConceptsDe novo variantsNDD genesCardiac patterningDe novo damaging variantsDamaging de novo variantsCHD genesDamaging variantsGenesProtein truncatingGenetic originNovo variantsGene mutationsPatterningRecent studiesDendritic developmentVariantsMutationsNeurogenesisSynaptogenesisBonferroni correctionSystems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects
Edwards JJ, Rouillard AD, Fernandez NF, Wang Z, Lachmann A, Shankaran SS, Bisgrove BW, Demarest B, Turan N, Srivastava D, Bernstein D, Deanfield J, Giardini A, Porter G, Kim R, Roberts AE, Newburger JW, Goldmuntz E, Brueckner M, Lifton RP, Seidman CE, Chung WK, Tristani-Firouzi M, Yost HJ, Ma’ayan A, Gelb BD. Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects. JACC Basic To Translational Science 2020, 5: 376-386. PMID: 32368696, PMCID: PMC7188873, DOI: 10.1016/j.jacbts.2020.01.012.Peer-Reviewed Original ResearchSmall GTPaseSpecific molecular functionsWAVE2 complexMolecular functionsCHD genesSignal transductionComplex proteinsHeart disease pathogenesisCardiac developmentCausative variantsGenetic variantsGTPaseNovo variantsGenesDisease pathogenesisPrimary driverVariantsWAVE2TransductionComplexesKnockdownRegulatorProteinRegulationPathogenesis
2019
De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Watkins WS, Hernandez EJ, Wesolowski S, Bisgrove BW, Sunderland RT, Lin E, Lemmon G, Demarest BL, Miller TA, Bernstein D, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Newburger JW, Seidman CE, Shen Y, Yost HJ, Yandell M, Tristani-Firouzi M. De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes. Nature Communications 2019, 10: 4722. PMID: 31624253, PMCID: PMC6797711, DOI: 10.1038/s41467-019-12582-y.Peer-Reviewed Original ResearchConceptsChromatin-modifying genesCilia-related genesGene classesDe novo variantsDistinct gene functionsDamaging de novo variantsBackground mutation rateGene burden analysisNovo variantsGene functionGenetic architectureRecessive formPediatric Cardiac Genomics ConsortiumSporadic congenital heart diseaseMode of inheritancePhenotypic landscapeGene pathwaysDisease genesGenomics ConsortiumMutation rateGenesRecessive genotypeDe novoCompound heterozygous genotypeDe novo forms
2017
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands
Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, Gaynor JW, Deanfield J, Giardini A, Porter GA, Srivastava D, Lo CW, Shen Y, Watkins WS, Yandell M, Yost HJ, Tristani-Firouzi M, Newburger JW, Roberts AE, Kim R, Zhao H, Kaltman JR, Goldmuntz E, Chung WK, Seidman JG, Gelb BD, Seidman CE, Lifton RP, Brueckner M. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nature Genetics 2017, 49: 1593-1601. PMID: 28991257, PMCID: PMC5675000, DOI: 10.1038/ng.3970.Peer-Reviewed Original ResearchMeSH KeywordsAdultAutistic DisorderCardiac MyosinsCase-Control StudiesChildExomeFemaleGene ExpressionGenetic Predisposition to DiseaseGenome-Wide Association StudyGrowth Differentiation Factor 1Heart Defects, CongenitalHeterozygoteHigh-Throughput Nucleotide SequencingHomozygoteHumansMaleMutationMyosin Heavy ChainsPedigreeRiskVascular Endothelial Growth Factor Receptor-3
2000
Of mice and men: Dissecting the genetic pathway that controls left‐right asymmetry in mice and humans
Schneider H, Brueckner M. Of mice and men: Dissecting the genetic pathway that controls left‐right asymmetry in mice and humans. American Journal Of Medical Genetics 2000, 97: 258-270. PMID: 11376437, DOI: 10.1002/1096-8628(200024)97:4<258::aid-ajmg1276>3.0.co;2-8.Peer-Reviewed Original ResearchMeSH KeywordsAbnormalities, MultipleAnimalsBody PatterningCiliaDyneinsEctodermEmbryonic and Fetal DevelopmentEndodermFetal ProteinsGastrulaGene Expression Regulation, DevelopmentalGenesGenes, HomeoboxGenes, LethalHomeodomain ProteinsHumansKinesinsMiceMice, Mutant StrainsMutationNotochordPhenotypeSpecies SpecificityTranscription FactorsConceptsLeft-right asymmetrySpontaneous mouse mutationGenetic pathwaysHuman homologueMouse mutationNode monociliaHuman mutationsHuman phenotypesFinal phenotypeOrchestrated mannerPathways resultsMouse phenotypeGenesLaterality determinationMutationsPhenotypeModel systemDifferent stepsMonociliaHomologuesCombination of analysisMicePathwayHuman developmentInitial asymmetry
1999
Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries
Supp D, Brueckner M, Kuehn M, Witte D, Lowe L, McGrath J, Corrales J, Potter S. Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 1999, 126: 5495-5504. PMID: 10556073, PMCID: PMC1797880, DOI: 10.1242/dev.126.23.5495.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAmino Acid SequenceAnimalsAxonemal DyneinsBinding SitesBody PatterningCatalytic DomainCiliaCloning, MolecularDyneinsFunctional LateralityGene Expression Regulation, DevelopmentalHeadMaleMiceMice, Inbred StrainsMolecular Sequence DataMutationNervous SystemSequence AnalysisSequence DeletionConceptsLeft-right dyneinLeft-right developmentLeft-right asymmetryEmbryonic day 8.0Microtubule-based motor proteinsAsymmetric expression patternLevel of sequenceComplete coding sequenceEmbryonic day 7.5Single amino acid differenceLeft-right specificationAmino acid differencesLeft-right axisLgl mutantsATP bindingConserved positionDay 8.0Inversus viscerum (iv) mouseCoding sequenceMotor proteinsDorsoventral axesExpression patternsGerm layersAcid differencesGenesGATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease
Pehlivan T, Pober B, Brueckner M, Garrett S, Slaugh R, Van Rheeden R, Wilson D, Watson M, Hing A. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. American Journal Of Medical Genetics 1999, 83: 201-206. PMID: 10096597, DOI: 10.1002/(sici)1096-8628(19990319)83:3<201::aid-ajmg11>3.0.co;2-v.Peer-Reviewed Original ResearchConceptsCardiac transcription factor genesZinc finger transcription factorHuman chromosome armsTranscription factor genesFinger transcription factorCardiac gene expressionChromosome armsTranscription factorsFactor genesGene expressionGATA4 geneInterstitial deletionGATA-4GenesLociFISH analysisSitu hybridizationDeletionHaploinsufficiencySubmicroscopic deletionRecent studiesPhenotype of patientsCellsMonosomyNormal karyotype
1998
Handed asymmetry in the mouse: Understanding how things go right (or left) by studying how they go wrong
Supp D, Brueckner M, Potter S. Handed asymmetry in the mouse: Understanding how things go right (or left) by studying how they go wrong. Seminars In Cell And Developmental Biology 1998, 9: 77-87. PMID: 9572117, DOI: 10.1006/scdb.1997.0186.Peer-Reviewed Original ResearchConceptsSevere morphological defectsAnalysis of genesAsymmetric expression patternLeft/right axisRight patterningGenetic pathwaysMouse mutationExpression patternsMorphological defectsDevelopmental asymmetryVertebratesImportance of regulationMutant micePattern formationRight axisGenesMutationsRegulationPathwayPatterningMiceDisruption
1996
The genetics of left-right development and heterotaxia
Bowers P, Brueckner M, Yost H. The genetics of left-right development and heterotaxia. Seminars In Perinatology 1996, 20: 577-588. PMID: 9090782, DOI: 10.1016/s0146-0005(96)80070-x.Peer-Reviewed Original ResearchConceptsLeft-right developmentMolecular genetic mechanismsPrimitive heart tubeSingle geneCardiac morphogenesisDifferent genesCardiac loopingHeart tubeGenesPhenotypeComplex groupHeterotaxiaMorphogenesisMost crucial stepCrucial stepGeneticsElucidationLoopingWide spectrumDevelopment resultsCongenital heart
1991
Establishment of Left‐Right Asymmetry in Vertebrates: Genetically Distinct Steps are Involved
Brueckner M, McGrath J, D'Eustachio P, Horwich A. Establishment of Left‐Right Asymmetry in Vertebrates: Genetically Distinct Steps are Involved. Novartis Foundation Symposia 1991, 162: 202-218. PMID: 1802643, DOI: 10.1002/9780470514160.ch12.Peer-Reviewed Original ResearchConceptsRestriction fragment length polymorphism (RFLP) markersFragment length polymorphism (AFLP) markersMouse chromosome 12Length polymorphism markersTiming of expressionLeft-right determinationLeft-right axisLeft-right asymmetryPositional cloningPolymorphism markersRecessive allelesGene productsPattern of inheritanceChromosome 12Developmental pathwaysLinkage analysisCardiac tubeFunction mutationsGenesMolecular analysisDevelopmental stepsFirst organAffected embryosVertebratesDistinct phenotypes