Featured Publications
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
Bilgüvar K, Öztürk A, Louvi A, Kwan KY, Choi M, Tatlı B, Yalnızoğlu D, Tüysüz B, Çağlayan A, Gökben S, Kaymakçalan H, Barak T, Bakırcıoğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yılmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçınkaya C, Kumandaş S, Topçu M, Özmen M, Šestan N, Lifton RP, State MW, Günel M. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 2010, 467: 207-210. PMID: 20729831, PMCID: PMC3129007, DOI: 10.1038/nature09327.Peer-Reviewed Original ResearchConceptsAbnormal cortical developmentWD repeat domain 62 (WDR62) geneSevere brain malformationsWhole-exome sequencingBrain abnormalitiesBrain malformationsCortical developmentMolecular pathogenesisCerebellar hypoplasiaWDR62 mutationsEmbryonic neurogenesisDiagnostic classificationMicrocephaly genesSmall family sizeGenetic heterogeneityWide spectrumRecessive mutationsPachygyriaPathogenesisHypoplasiaNeocortexNeurogenesisAbnormalitiesMalformationsMutationsRecessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration
Bilguvar K, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO, Baranoski JF, Erturk O, Yalcinkaya C, Karacorlu M, Dincer A, Johnson MH, Mane S, Chandra SS, Louvi A, Boggon TJ, Lifton RP, Horwich AL, Gunel M. Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 3489-3494. PMID: 23359680, PMCID: PMC3587195, DOI: 10.1073/pnas.1222732110.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge of OnsetAmino Acid SequenceBase SequenceChild, PreschoolExomeFemaleGenes, RecessiveHomozygoteHumansHydrolysisMaleModels, MolecularMolecular Sequence DataMutation, MissenseNerve DegenerationNeuronsPedigreeProtein BindingSequence Analysis, DNASubstrate SpecificitySyndromeThermodynamicsUbiquitinUbiquitin ThiolesteraseConceptsUbiquitin C-terminal hydrolase L1Upper motor neuron dysfunctionMotor neuron dysfunctionProgressive neurodegenerative syndromeEarly-onset progressive neurodegenerationChildhood-onset blindnessWhole-exome sequencingNeuron dysfunctionHomozygous missense mutationIndex caseNervous systemProgressive neurodegenerationNeurodegenerative syndromeCerebellar ataxiaHydrolase activityNear complete lossComplete lossAffected individualsConsanguineous unionsMissense mutationsRecessive lossHomozygosity mappingProper positioningReduced affinitySpasticityPPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
Barak T, Ristori E, Ercan-Sencicek AG, Miyagishima DF, Nelson-Williams C, Dong W, Jin SC, Prendergast A, Armero W, Henegariu O, Erson-Omay EZ, Harmancı AS, Guy M, Gültekin B, Kilic D, Rai DK, Goc N, Aguilera SM, Gülez B, Altinok S, Ozcan K, Yarman Y, Coskun S, Sempou E, Deniz E, Hintzen J, Cox A, Fomchenko E, Jung SW, Ozturk AK, Louvi A, Bilgüvar K, Connolly ES, Khokha MK, Kahle KT, Yasuno K, Lifton RP, Mishra-Gorur K, Nicoli S, Günel M. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans. Nature Medicine 2021, 27: 2165-2175. PMID: 34887573, PMCID: PMC8768030, DOI: 10.1038/s41591-021-01572-7.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesPeptidyl-prolyl cis-transPathogenesis of IAContribution of variantsCommon genetic variantsVertebrate modelDeleterious mutationsWnt activatorAssociation studiesWhole-exome sequencingSignificant enrichmentGenetic variantsWntAngiogenesis regulatorsMutationsGene mutationsBrain angiogenesisIntracranial aneurysm ruptureJMJD6AngiogenesisCerebrovascular morphologyCerebrovascular integrityIntracerebral hemorrhageAneurysm ruptureVariants
2024
Exploring molecular and cellular mechanisms and phenotypic characteristics of NAGLU Arg234Gly and Asp312Asn variants
Kaymakcalan Celebiler H, Barak T, Rai D, Kaya I, Erbilgin S, Cikili Uytun M, Oztop D, Gumus H, Per H, Ceylaner S, Bozkurt I, Kontaridis M, Bilguvar K, Akhun N, Kilincaslan A, Caglayan A, Erson-Omay E, Gunel M, Ercan-Sencicek A. Exploring molecular and cellular mechanisms and phenotypic characteristics of NAGLU Arg234Gly and Asp312Asn variants. Molecular Syndromology 2024, 1-15. DOI: 10.1159/000542367.Peer-Reviewed Original ResearchWhole-exome sequencingStandard Sanger sequencingMucopolysaccharidosis type IIIBExome sequencingProgressive neurodegenerative disorderConsanguineous familySanger sequencingNAGLU genePhenotypic characteristicsMagnetic resonance imagingEnzymatic assayNeurodegenerative disordersAffected individualsLoss of activityNeurodegenerative symptomsAutosomal recessive lysosomal disorderCellular mechanismsVariantsLysosomal disorderEnzymeNormal MRI findingsSequenceMPS IIIBMRI findingsType IIIB
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
2021
NIMG-64. TYPE OF BONY INVOLVEMENT PREDICTS GENOMIC SUBGROUP IN SPHENOID WING MENINGIOMAS
Jin L, Youngblood M, Gupte T, Vetsa S, Nadar A, Barak T, Yalcin K, Aguilera S, Mishra-Gorur K, Blondin N, Omay S, Pointdujour-Lim R, Judson B, Alperovich M, Aboian M, McGuone D, Gunel M, Erson-Omay Z, Fulbright R, Moliterno J. NIMG-64. TYPE OF BONY INVOLVEMENT PREDICTS GENOMIC SUBGROUP IN SPHENOID WING MENINGIOMAS. Neuro-Oncology 2021, 23: vi144-vi144. PMCID: PMC8598770, DOI: 10.1093/neuonc/noab196.562.Peer-Reviewed Original ResearchSphenoid wing meningiomaSpheno-orbital meningiomasBony involvementTRAF7 mutationsTumor invasionGenomic subgroupsPre-operative clinical featuresYale-New Haven HospitalAdditional clinical variablesSubset of tumorsPre-operative predictionLogistic regression modelsWhole-exome sequencingClinical featuresClinical variablesGrade IIPredictive logistic regression modelRecurrence patternsMolecular subtypesClinical implicationsExome sequencingHyperostosisMeningiomasTumorsGenomic driversType of bony involvement predicts genomic subgroup in sphenoid wing meningiomas
Jin L, Youngblood MW, Gupte TP, Vetsa S, Nadar A, Barak T, Yalcin K, Aguilera SM, Mishra-Gorur K, Blondin NA, Gorelick E, Omay SB, Pointdujour-Lim R, Judson BL, Alperovich M, Aboian MS, McGuone D, Gunel M, Erson-Omay Z, Fulbright RK, Moliterno J. Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas. Journal Of Neuro-Oncology 2021, 154: 237-246. PMID: 34350560, DOI: 10.1007/s11060-021-03819-2.Peer-Reviewed Original ResearchConceptsSpheno-orbital meningiomasSphenoid wing meningiomaBony involvementTRAF7 mutationsGenomic subgroupsPre-operative clinical featuresTumor invasionYale-New Haven HospitalAdditional clinical variablesSubset of tumorsPre-operative predictionWhole-exome sequencingBone involvementBone invasionClinical featuresClinical variablesGrade IIMolecular subtypesRecurrence patternsClinical implicationsHyperostosisExome sequencingMeningiomasTumorsGenomic drivers
2020
Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus
Jin SC, Dong W, Kundishora AJ, Panchagnula S, Moreno-De-Luca A, Furey CG, Allocco AA, Walker RL, Nelson-Williams C, Smith H, Dunbar A, Conine S, Lu Q, Zeng X, Sierant MC, Knight JR, Sullivan W, Duy PQ, DeSpenza T, Reeves BC, Karimy JK, Marlier A, Castaldi C, Tikhonova IR, Li B, Peña HP, Broach JR, Kabachelor EM, Ssenyonga P, Hehnly C, Ge L, Keren B, Timberlake AT, Goto J, Mangano FT, Johnston JM, Butler WE, Warf BC, Smith ER, Schiff SJ, Limbrick DD, Heuer G, Jackson EM, Iskandar BJ, Mane S, Haider S, Guclu B, Bayri Y, Sahin Y, Duncan CC, Apuzzo MLJ, DiLuna ML, Hoffman EJ, Sestan N, Ment LR, Alper SL, Bilguvar K, Geschwind DH, Günel M, Lifton RP, Kahle KT. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nature Medicine 2020, 26: 1754-1765. PMID: 33077954, PMCID: PMC7871900, DOI: 10.1038/s41591-020-1090-2.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusPoor neurodevelopmental outcomesPost-surgical patientsCerebrospinal fluid accumulationNeural stem cell biologyGenetic disruptionWhole-exome sequencingPrimary pathomechanismEarly brain developmentNeurodevelopmental outcomesHigh morbidityCSF diversionMutation burdenFluid accumulationBrain ventriclesCH casesBrain developmentDe novo mutationsPatientsExome sequencingCSF dynamicsDisease mechanismsHydrocephalusNovo mutationsCell types
2018
P04.60 Genomic profile of tumorigenesis in a patient with Turcot syndrome
Karschnia P, Erson-Omay E, Huttner A, Fulbright R, Günel M, Baehring J. P04.60 Genomic profile of tumorigenesis in a patient with Turcot syndrome. Neuro-Oncology 2018, 20: iii293-iii293. PMCID: PMC6143975, DOI: 10.1093/neuonc/noy139.294.Peer-Reviewed Original ResearchWhole-exome sequencingEndometrial carcinomaTurcot syndromeBrain tumorsMicrosatellite instabilityMMR genesSecond hitSomatic missense mutationsMissense mutationsLeft frontal tumorPrimary brain tumorsPatient's brain tumorMismatch repair deficiencyMMR-deficient tumorsExpression of MSH6Heterozygous germline mutationsHeterozygous germline missense mutationRight hemiparesisSubtotal resectionUterine adenocarcinomaMetachronous tumorsFrontal tumorGermline missense mutationAbdominal tumorsFamily history
2017
Exome analysis of the evolutionary path of hepatocellular adenoma-carcinoma transition, vascular invasion and brain dissemination
Vilarinho S, Erson-Omay E, Mitchell-Richards K, Cha C, Nelson-Williams C, Harmancı AS, Yasuno K, Günel M, Taddei TH. Exome analysis of the evolutionary path of hepatocellular adenoma-carcinoma transition, vascular invasion and brain dissemination. Journal Of Hepatology 2017, 67: 186-191. PMID: 28323122, PMCID: PMC5497691, DOI: 10.1016/j.jhep.2017.03.009.Peer-Reviewed Original ResearchConceptsAdenoma-carcinoma transitionHepatocellular adenomaBrain metastasesHepatocellular carcinomaVascular invasionTumor thrombusCatenin beta 1Rare benign liver tumorMultifocal hepatic lesionsAcute abdominal painBenign liver tumorsPeripheral blood leucocytesSomatic mutationsWhole-exome sequencingParaffin-embedded samplesBrain disseminationAbdominal painLeft hepatectomyMajor complicationsLiver diseaseSpontaneous hemorrhageLeft lobeDisease progressionBlood leucocytesLiver tumorsLongitudinal analysis of treatment-induced genomic alterations in gliomas
Erson-Omay EZ, Henegariu O, Omay SB, Harmancı AS, Youngblood MW, Mishra-Gorur K, Li J, Özduman K, Carrión-Grant G, Clark VE, Çağlar C, Bakırcıoğlu M, Pamir MN, Tabar V, Vortmeyer AO, Bilguvar K, Yasuno K, DeAngelis LM, Baehring JM, Moliterno J, Günel M. Longitudinal analysis of treatment-induced genomic alterations in gliomas. Genome Medicine 2017, 9: 12. PMID: 28153049, PMCID: PMC5290635, DOI: 10.1186/s13073-017-0401-9.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsChromosome AberrationsCombined Modality TherapyDisease ProgressionDNA Mismatch RepairDNA Mutational AnalysisDNA, NeoplasmExomeFemaleGeneral SurgeryGenome, HumanGenomicsGlioblastomaHumansImmunotherapyLongitudinal StudiesMiddle AgedMutationNeoplasm Recurrence, LocalPrecision MedicineRadiotherapyTreatment OutcomeConceptsWhole-exome sequencingMismatch repair deficiencyImmune checkpoint inhibitionMalignant brain tumorsMolecular changesLongitudinal analysisMedian survivalCheckpoint inhibitionSubsequent recurrenceMaximal resectionStandard treatmentBackgroundGlioblastoma multiformeBrain tumorsTumor-normal pairsFavorable responsePrimary GBMIndividual tumorsConclusionsOur studyPrecision therapyPersonalized treatmentGenomic profilingRepair deficiencyGenomic alterationsGenomic profilesTherapy
2016
Familial occurrence of brain arteriovenous malformation: a novel ACVRL1 mutation detected by whole exome sequencing.
Yılmaz B, Toktaş ZO, Akakın A, Işık S, Bilguvar K, Kılıç T, Günel M. Familial occurrence of brain arteriovenous malformation: a novel ACVRL1 mutation detected by whole exome sequencing. Journal Of Neurosurgery 2016, 126: 1879-1883. PMID: 27611203, DOI: 10.3171/2016.6.jns16665.Peer-Reviewed Original ResearchConceptsBrain arteriovenous malformationsHereditary hemorrhagic telangiectasiaWhole-exome sequencingArteriovenous malformationsExome sequencingWhole-exome sequencing analysisSpinal arteriovenous malformationsDiagnostic classification schemesExome sequencing analysisComprehensive genomic characterizationConclusion Study resultsCranial MRIDirect Sanger sequencingHemorrhagic telangiectasiaBlood samplesFamilial occurrenceHeterozygous mutationsACVRL1 mutationsPatientsThree SiblingsFourth siblingVariant segregationSanger sequencingMalformationsSiblings
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
Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations
Vilarinho S, Erson-Omay EZ, Harmanci AS, Morotti R, Carrion-Grant G, Baranoski J, Knisely AS, Ekong U, Emre S, Yasuno K, Bilguvar K, Günel M. Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. Journal Of Hepatology 2014, 61: 1178-1183. PMID: 25016225, DOI: 10.1016/j.jhep.2014.07.003.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceATP Binding Cassette Transporter, Subfamily B, Member 11ATP-Binding Cassette TransportersBase SequenceBeta CateninCarcinoma, HepatocellularCholestasis, IntrahepaticDNA, NeoplasmFemaleGerm-Line MutationHumansInfantLiver NeoplasmsMolecular Sequence DataMutationMutation, MissenseNF-E2-Related Factor 2Sequence Homology, Amino AcidConceptsBile salt export pumpWhole-exome sequencingHepatocellular carcinomaMonths of ageNFE2L2 mutationsABCB11 mutationsSomatic CTNNB1Background liver parenchymaPediatric hepatocellular carcinomaNew onsetSomatic driver mutationsBSEP expressionLiver parenchymaHCC tissuesHepatocellular carcinogenesisWES analysisExport pumpDriver mutationsCTNNB1 mutationsExome sequencingChild's diagnosisClonality analysisGermline DNAPossible genetic basisEarly childhoodHomozygous loss of DIAPH1 is a novel cause of microcephaly in humans
Ercan-Sencicek AG, Jambi S, Franjic D, Nishimura S, Li M, El-Fishawy P, Morgan TM, Sanders SJ, Bilguvar K, Suri M, Johnson MH, Gupta AR, Yuksel Z, Mane S, Grigorenko E, Picciotto M, Alberts AS, Gunel M, Šestan N, State MW. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. European Journal Of Human Genetics 2014, 23: 165-172. PMID: 24781755, PMCID: PMC4297910, DOI: 10.1038/ejhg.2014.82.Peer-Reviewed Original ResearchConceptsCell divisionFamily-based linkage analysisLinkage analysisRho effector proteinsLinear actin filamentsMaintenance of polarityMitotic cell divisionHigh-throughput sequencingRare genetic variantsHuman neuronal precursor cellsParametric multipoint linkage analysisActivation of GTPNeuronal precursor cellsFormin familyMammalian DiaphanousEffector proteinsMultipoint linkage analysisSpindle formationActin filamentsNonsense alterationWhole-exome sequencingHuman pathologiesNeuroepithelial cellsGenetic variantsHomozygous lossAutosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: Expansion of the facial and neuroimaging features
Tüysüz B, Bilguvar K, Koçer N, Yalçınkaya C, Çağlayan O, Gül E, Şahin S, Çomu S, Günel M. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: Expansion of the facial and neuroimaging features. American Journal Of Medical Genetics Part A 2014, 164: 1677-1685. PMID: 24700674, DOI: 10.1002/ajmg.a.36514.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsBrainChildDNA Mutational AnalysisDNA-Binding ProteinsFaciesFemaleGenes, RecessiveGenetic Association StudiesHomozygoteHumansMagnetic Resonance ImagingMaleMutationNeuroimagingPedigreePhenotypeQuadriplegiaRNA-Binding ProteinsSiblingsConceptsAdaptor protein complex 4Tetraplegic cerebral palsySevere intellectual disabilitySpastic tetraplegiaCerebral palsySpastic tetraplegic cerebral palsyIntellectual disabilityStereotypic laughterCranial imaging findingsWhite matter volumeWhole-exome sequencingNovel homozygous mutationAsymmetrical ventriculomegalyCranial MRIImaging findingsClinical findingsNeuroimaging featuresBrain abnormalitiesCommon findingCorpus callosumAutosomal recessive phenotypePairs of siblingsPatientsSimilar facial featuresMatter volumeExome 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