Featured Publications
The quest to unravel the complex genomics of intracranial aneurysms
Barak T, Günel M. The quest to unravel the complex genomics of intracranial aneurysms. Nature Cardiovascular Research 2022, 1: 281-282. PMID: 39196131, DOI: 10.1038/s44161-022-00051-7.Commentaries, Editorials and Letters
2022
Mutation 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
2018
Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation
Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu Q, Timberlake AT, Dong W, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang J, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, López-Giráldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, Kahle KT. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. Neuron 2018, 101: 429-443.e4. PMID: 30578106, PMCID: PMC10292091, DOI: 10.1016/j.neuron.2018.11.041.Peer-Reviewed Original ResearchConceptsChromatin modifiersVascular developmentSpecification of arteriesDeep venous systemNormal vascular developmentParent-offspring triosSignaling GenesGalen malformationDamaging mutationsGenesMutationsEssential roleArterio-venous malformationsCutaneous vascular abnormalitiesNovo mutationsExome sequencingDisease biologyIncomplete penetranceVariable expressivityVascular abnormalitiesVenous systemMutation carriersArterial bloodMutation burdenClinical implications
2016
Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly
Jerber J, Zaki MS, Al-Aama JY, Rosti RO, Ben-Omran T, Dikoglu E, Silhavy JL, Caglar C, Musaev D, Albrecht B, Campbell KP, Willer T, Almuriekhi M, Çağlayan A, Vajsar J, Bilgüvar K, Ogur G, Jamra R, Günel M, Gleeson JG. Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. American Journal Of Human Genetics 2016, 99: 1181-1189. PMID: 27773428, PMCID: PMC5097947, DOI: 10.1016/j.ajhg.2016.09.007.Peer-Reviewed Original ResearchConceptsCongenital muscular dystrophyCobblestone lissencephalyOvermigration of neuronsBiallelic mutationsMuscular dystrophyTMTC3Affected individualsWalker-Warburg syndromeMembrane componentsSevere brain malformationsBasement membrane componentsFukuyama congenital muscular dystrophyMuscle creatine phosphokinaseEye defectsMutationsGenesRecessive formGenetic disordersGlial cellsMinimal eyeMuscle involvementCortical dysplasiaBrain malformationsEye anomaliesCreatine phosphokinase
2015
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, Harrell TM, McMillin MJ, Wiszniewski W, Gambin T, Akdemir Z, Doheny K, Scott AF, Avramopoulos D, Chakravarti A, Hoover-Fong J, Mathews D, Witmer PD, Ling H, Hetrick K, Watkins L, Patterson KE, Reinier F, Blue E, Muzny D, Kircher M, Bilguvar K, López-Giráldez F, Sutton VR, Tabor HK, Leal SM, Gunel M, Mane S, Gibbs RA, Boerwinkle E, Hamosh A, Shendure J, Lupski JR, Lifton RP, Valle D, Nickerson DA, Genomics C, Bamshad MJ. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. American Journal Of Human Genetics 2015, 97: 199-215. PMID: 26166479, PMCID: PMC4573249, DOI: 10.1016/j.ajhg.2015.06.009.Peer-Reviewed Original ResearchConceptsMendelian phenotypesGenetic basisLarge-scale whole-exome sequencingMendelian conditionsGene functionGene regulationGenomic dataWhole-exome sequencingMendelian GenomicsGenesPhenotypic characterizationNovel mechanismExtensive clinical variabilityGenetic variantsPhenotypePervasive sharingBiological mechanismsSequencingNew therapeuticsSuch discoveriesFamilyDiscoveryHuman healthGenomicsClinical variability
2014
Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders
Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud I, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders. Science 2014, 343: 506-511. PMID: 24482476, PMCID: PMC4157572, DOI: 10.1126/science.1247363.Peer-Reviewed Original ResearchConceptsHereditary spastic paraplegiaFurther candidate genesMotor neuron diseaseNeurodegenerative disordersGene discoveryHSP genesGenetic basisCandidate genesNetwork analysisNeuron diseaseCellular transportWhole-exome sequencingNeurodegenerative motor neuron diseaseProgressive age-dependent lossAge-dependent lossGenesMechanistic understandingMotor tract functionCommon neurodegenerative disorderFraction of casesTract functionGenetic diagnosisSpastic paraplegiaGlobal viewDisease
2012
Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion
Emre Onat O, Gulsuner S, Bilguvar K, Nazli Basak A, Topaloglu H, Tan M, Tan U, Gunel M, Ozcelik T. Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. European Journal Of Human Genetics 2012, 21: 281-285. PMID: 22892528, PMCID: PMC3573203, DOI: 10.1038/ejhg.2012.170.Peer-Reviewed Original ResearchConceptsC-terminal transmembrane regionATPase domainNext-generation sequencingTransmembrane regionHomozygous regionsHomozygosity mappingAffected individualsATP8A2Novel missense variantChromosome 13q12Missense mutationsATP8A2 geneSegregation analysisConsanguineous familyMissense variantsUnrelated individualsMutationsMental retardationQuadrupedal locomotionGenesDysequilibrium syndromeSequencingTranslocationATPaseNovoThe Centers for Mendelian Genomics: A new large‐scale initiative to identify the genes underlying rare Mendelian conditions
Bamshad MJ, Shendure JA, Valle D, Hamosh A, Lupski JR, Gibbs RA, Boerwinkle E, Lifton RP, Gerstein M, Gunel M, Mane S, Nickerson DA, Genomics O. The Centers for Mendelian Genomics: A new large‐scale initiative to identify the genes underlying rare Mendelian conditions. American Journal Of Medical Genetics Part A 2012, 158A: 1523-1525. PMID: 22628075, PMCID: PMC3702263, DOI: 10.1002/ajmg.a.35470.Peer-Reviewed Original ResearchConceptsWhole-genome sequencingMendelian GenomicsMendelian disordersHuman genetics communityNext-generation exome sequencingExome sequencingGenomicsMendelian phenotypesGenome sequencingGenetics communityRare Mendelian conditionsMendelian conditionsGenesSequencingNew powerful toolPowerful toolLarge fractionPhenotypeLarge-scale initiativesDiscoveryIdentification
2011
Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism
Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim YS, Fishman DO, Raubeson MJ, Song Y, Yasuno K, Ho WS, Bilguvar K, Glessner J, Chu SH, Leckman JF, King RA, Gilbert DL, Heiman GA, Tischfield JA, Hoekstra PJ, Devlin B, Hakonarson H, Mane SM, Günel M, State MW. Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism. Biological Psychiatry 2011, 71: 392-402. PMID: 22169095, PMCID: PMC3282144, DOI: 10.1016/j.biopsych.2011.09.034.Peer-Reviewed Original ResearchConceptsCopy number variationsRare copy number variationsNovel risk regionsEnrichment of genesGamma-aminobutyric acid receptor genesNervous system developmentEtiology of TSParent-child triosRare copy number variantsCopy number variantsGene mappingPathway analysisDe novo eventsAxon guidanceCell adhesionMolecular pathwaysNumber variationsRelevant pathwaysCNV analysisNumber variantsGenesReceptor geneDe novoNovo eventsPathwayHomozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
Gulsuner S, Tekinay AB, Doerschner K, Boyaci H, Bilguvar K, Unal H, Ors A, Onat OE, Atalar E, Basak AN, Topaloglu H, Kansu T, Tan M, Tan U, Gunel M, Ozcelik T. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Research 2011, 21: 1995-2003. PMID: 21885617, PMCID: PMC3227090, DOI: 10.1101/gr.126110.111.Peer-Reviewed Original ResearchConceptsBeta-propeller domainPrivate missense mutationsLarge consanguineous familyThird geneBEACH domainTransmembrane proteinHomozygous regionsHomozygosity mappingGenomic sequencingWDR81Chromosome 17p13.1Missense mutationsQuadrupedal locomotionConsanguineous familyTargeted sequencingGenesSequencingRare phenotypeMorphological abnormalitiesBiological basisMutationsAffected individualsCell layerParticular atrophyFamily
2010
L-Histidine Decarboxylase and Tourette's Syndrome
Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O'Roak BJ, Mason CE, Abbott T, Gupta A, King RA, Pauls DL, Tischfield JA, Heiman GA, Singer HS, Gilbert DL, Hoekstra PJ, Morgan TM, Loring E, Yasuno K, Fernandez T, Sanders S, Louvi A, Cho JH, Mane S, Colangelo CM, Biederer T, Lifton RP, Gunel M, State MW. L-Histidine Decarboxylase and Tourette's Syndrome. New England Journal Of Medicine 2010, 362: 1901-1908. PMID: 20445167, PMCID: PMC2894694, DOI: 10.1056/nejmoa0907006.Peer-Reviewed Original ResearchConceptsRare functional mutationsL-histidine decarboxylaseRate-limiting enzymeHDC geneTwo-generation pedigreeFunctional mutationsStrong genetic contributionHistamine biosynthesisAnalysis of linkageGenetic contributionModel systemRisk allelesDevelopmental neuropsychiatric disordersDecarboxylaseBiosynthesisGenesTourette syndromeMutationsAllelesEnzymeInheritanceNeuropsychiatric disordersPedigreeStabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development
He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W. Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development. Science Signaling 2010, 3: ra26. PMID: 20371769, PMCID: PMC3052863, DOI: 10.1126/scisignal.2000722.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCardiovascular SystemEndothelial CellsFluorescent Antibody Technique, IndirectGene DeletionGene Expression ProfilingGene Knockdown TechniquesHematopoiesisHumansImmunoblottingImmunohistochemistryImmunoprecipitationMiceReverse Transcriptase Polymerase Chain ReactionSignal TransductionVascular Endothelial Growth Factor Receptor-2ConceptsCarboxyl-terminal domainVascular endothelial growth factor receptor 2Vascular developmentHuman vascular malformationsCerebral cavernous malformation 3Early embryonic stagesCerebral cavernous malformationsEndothelial cell-specific deletionApoptotic stimuliCell-specific deletionVivo functionEmbryonic angiogenesisEndothelial growth factor receptor 2Unknown functionVEGF stimulationVEGFR2 signalingEmbryonic stagesMessenger RNASmooth muscle cellsGrowth factor receptor 2DeletionCCM3 genesFactor receptor 2Muscle cellsGenes
2006
Molecular Genetic Analysis of Two Large Kindreds With Intracranial Aneurysms Demonstrates Linkage to 11q24-25 and 14q23-31
Ozturk AK, Nahed BV, Bydon M, Bilguvar K, Goksu E, Bademci G, Guclu B, Johnson MH, Amar A, Lifton RP, Gunel M. Molecular Genetic Analysis of Two Large Kindreds With Intracranial Aneurysms Demonstrates Linkage to 11q24-25 and 14q23-31. Stroke 2006, 37: 1021-1027. PMID: 16497978, DOI: 10.1161/01.str.0000206153.92675.b9.Peer-Reviewed Original ResearchConceptsGenome-wide linkage analysisMolecular genetic analysisGenetic analysisSusceptibility genesLinkage analysisSimple Mendelian traitPolymorphic microsatellite markersSignificant LOD scoreGenomic regionsMendelian traitsMicrosatellite markersCandidate lociGene chipOutlier approachOdds (LOD) scoreGenesChromosome 11q24Chromosome 11qAvailable family membersLOD scoreGenetic heterogeneityIa geneLociSib pairsGenetic factors
2005
Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations
Guclu B, Ozturk AK, Pricola KL, Seker A, Ozek M, Gunel M. Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations. Stroke 2005, 36: 2479-2480. PMID: 16239636, DOI: 10.1161/01.str.0000183616.99139.d3.Peer-Reviewed Original ResearchMeSH KeywordsApoptosis Regulatory ProteinsBlood VesselsCarrier ProteinsChildDNA Mutational AnalysisExonsFamily HealthFemaleFrameshift MutationGene Expression RegulationHumansIntracranial Arteriovenous MalformationsKRIT1 ProteinMaleMembrane ProteinsMicrotubule-Associated ProteinsModels, GeneticMutationPedigreeProto-Oncogene ProteinsConceptsMutational analysisCerebral cavernous malformationsDistinct genetic originsCCM genesCerebral venous malformationSuch mutationsCausative genesUnique familyFrameshift mutationGenesGenetic originCCM1 geneCommon originMutationsFamilyVenous malformationsPathogenetic mechanismsCavernous malformationsMembersDistinct biologyPDCD10BiologyExon 19KRIT1Different pathogenetic mechanisms
2004
Mapping a Mendelian Form of Intracranial Aneurysm to 1p34.3-p36.13
Nahed BV, Seker A, Guclu B, Ozturk AK, Finberg K, Hawkins AA, DiLuna ML, State M, Lifton RP, Gunel M. Mapping a Mendelian Form of Intracranial Aneurysm to 1p34.3-p36.13. American Journal Of Human Genetics 2004, 76: 172-179. PMID: 15540160, PMCID: PMC1196421, DOI: 10.1086/426953.Peer-Reviewed Original ResearchConceptsMendelian formsSimple tandem repeatsIdentification of pathwaysHigh penetranceSingle geneUnderlying genesSingle nucleotide polymorphismsSingle locusTandem repeatsCandidate intervalGenomewide studiesDisease locusAnalysis of linkageLOD scoreLociRare familiesSignificant linkageRelative pairsGenesDominant traitEnvironmental factorsLarge kindredPenetranceRepeatsTraits
1998
Molecular Biology of Cerebrovascular Diseases
Gunel M, Awad I, Lifton R. Molecular Biology of Cerebrovascular Diseases. 1998, 163-173. DOI: 10.1007/978-1-4613-9350-4_15.Peer-Reviewed Original ResearchMolecular biologyIdentification of genesCerebrovascular diseaseMolecular geneticsMolecular mechanismsScope of neurosurgeryNovel therapeutic strategiesBiologyNew insightsPathologic angiogenesisInherited predispositionTherapeutic strategiesBasic mechanismsPreclinical diagnosisDiseaseGenesGeneticsMechanismAngiogenesisIschemiaPatientsPathophysiologyPathogenesisNew opportunitiesDiagnosis
1996
Genetic Heterogeneity of Inherited Cerebral Cavernous Malformation
Günel M, Awad I, Finberg K, Steinberg G, Craig H, Cepeda O, Nelson-Williams C, Lifton R. Genetic Heterogeneity of Inherited Cerebral Cavernous Malformation. Neurosurgery 1996, 38: 1265-1271. DOI: 10.1227/00006123-199606000-00059.Peer-Reviewed Original ResearchConceptsGenetic analysisCauses of CCMsCerebral cavernous malformationsHuman chromosome 7Second geneIndependent inheritanceMutant geneChromosome 7Genetic markersGenesLong armGenetic heterogeneityMutationsCavernous malformationsInheritanceFamilyAutosomal dominant transmissionClinical featuresGenetic testingDominant transmissionKindredsMarkersNon-Hispanic familiesMalformationsDisordersGenetic heterogeneity of inherited cerebral cavernous malformation.
Günel M, Awad I, Finberg K, Steinberg G, Craig H, Cepeda O, Carol N, Lifton R. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996, 38: 1265-71. PMID: 8727164, DOI: 10.1097/00006123-199606000-00059.Peer-Reviewed Original ResearchConceptsGenetic analysisCauses of CCMsCerebral cavernous malformationsHuman chromosome 7Second geneIndependent inheritanceMutant geneChromosome 7Genetic markersGenesLong armGenetic heterogeneityMutationsCavernous malformationsInheritanceFamilyAutosomal dominant transmissionClinical featuresGenetic testingDominant transmissionKindredsMarkersNon-Hispanic familiesMalformationsDisorders