2021
PPIL4 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
2020
METAP1 mutation is a novel candidate for autosomal recessive intellectual disability
Caglayan AO, Aktar F, Bilguvar K, Baranoski JF, Akgumus GT, Harmanci AS, Erson-Omay EZ, Yasuno K, Caksen H, Gunel M. METAP1 mutation is a novel candidate for autosomal recessive intellectual disability. Journal Of Human Genetics 2020, 66: 215-218. PMID: 32764695, PMCID: PMC7785574, DOI: 10.1038/s10038-020-0820-0.Peer-Reviewed Original ResearchConceptsEssential proteinsAutosomal recessive intellectual disabilityRecessive intellectual disabilityMethionine aminopeptidase 1Genomic analysisHomozygous nonsense mutationFunction mutationsNovel homozygous nonsense mutationNonsense mutationAminopeptidase 1Novel candidatesNeuronal functionMutationsMolecular pathogenesisProteinIntellectual disabilityGenome testingEukaryotesNovel etiologyMetAP1GenesNeurologic impairmentCommon diseasePathwayCells
2018
Loss of Protocadherin‐12 Leads to Diencephalic‐Mesencephalic Junction Dysplasia Syndrome
Guemez‐Gamboa A, Çağlayan AO, Stanley V, Gregor A, Zaki M, Saleem SN, Musaev D, McEvoy‐Venneri J, Belandres D, Akizu N, Silhavy JL, Schroth J, Rosti RO, Copeland B, Lewis SM, Fang R, Issa MY, Per H, Gumus H, Bayram AK, Kumandas S, Akgumus GT, Erson‐Omay E, Yasuno K, Bilguvar K, Heimer G, Pillar N, Shomron N, Weissglas‐Volkov D, Porat Y, Einhorn Y, Gabriel S, Ben‐Zeev B, Gunel M, Gleeson JG. Loss of Protocadherin‐12 Leads to Diencephalic‐Mesencephalic Junction Dysplasia Syndrome. Annals Of Neurology 2018, 84: 638-647. PMID: 30178464, PMCID: PMC6510237, DOI: 10.1002/ana.25327.Peer-Reviewed Original ResearchConceptsBrainstem malformationDysplasia syndromeEndothelial cellsBiallelic mutationsAutosomal recessive malformationSuch pathogenic variantsCharacteristic clinical presentationPatient-derived induced pluripotent stem cellsWhite matter tractsAnn NeurolAppendicular spasticityBrain calcificationClinical presentationPoor outcomeAxial hypotoniaPsychomotor disabilityProgressive microcephalyTract defectsPathogenic variantsPhenotypic spectrumPatientsCraniofacial dysmorphismBrain imagingNeural precursorsProtein expressionGenotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome
Yilmaz S, Alkaya D, Kasapçopur Ö, Barut K, Akdemir ES, Celen C, Youngblood MW, Yasuno K, Bilguvar K, Günel M, Tüysüz B. Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome. Molecular Genetics & Genomic Medicine 2018, 6: 230-248. PMID: 29397575, PMCID: PMC5902402, DOI: 10.1002/mgg3.364.Peer-Reviewed Original ResearchConceptsCoxa vara-pericarditis (CACP) syndromeCoxa varaCommon childhood rheumatic diseaseIncreased pain levelSevere hip involvementChildhood rheumatic diseasesJuvenile idiopathic arthritisDevelopmental coxa varaRare autosomal recessive conditionYears of ageUnrelated familiesWhole-exome sequencingAutosomal recessive conditionHip involvementIdiopathic arthritisMost patientsPain levelsRadiological findingsPleural effusionJoint involvementNoninflammatory arthropathyRheumatic diseasesNovel genomic alterationsFirst symptomsCACP syndrome
2017
ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features
Çağlayan AO, Sezer RG, Kaymakçalan H, Ulgen E, Yavuz T, Baranoski JF, Bozaykut A, Harmanci AS, Yalcin Y, Youngblood MW, Yasuno K, Bilgüvar K, Gunel M. ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. Molecular Case Studies 2017, 3: a001859. PMID: 28630369, PMCID: PMC5593152, DOI: 10.1101/mcs.a001859.Peer-Reviewed Original ResearchConceptsNovel homozygous frameshift mutationWk of gestationHomozygous pathogenic variantNovel disease-causing genesPhenotypic featuresHomozygous frameshift mutationWhole-exome sequencingHeterozygous family membersUnrelated consanguineous familiesEchocardiographic examinationDisease groupPrimary cardiomyopathyMale infantHypertrophic cardiomyopathyRoutine diagnostic toolCardiac diseaseCardiac abnormalitiesMale fetusesCardiomyopathyPathogenic variantsGenetic testingDysmorphic featuresGene mutationsPast historyDisease-causing genesExome 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 tumorsIntegrated genomic analyses of de novo pathways underlying atypical meningiomas
Harmancı AS, Youngblood MW, Clark VE, Coşkun S, Henegariu O, Duran D, Erson-Omay EZ, Kaulen LD, Lee TI, Abraham BJ, Simon M, Krischek B, Timmer M, Goldbrunner R, Omay SB, Baranoski J, Baran B, Carrión-Grant G, Bai H, Mishra-Gorur K, Schramm J, Moliterno J, Vortmeyer AO, Bilgüvar K, Yasuno K, Young RA, Günel M. Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nature Communications 2017, 8: 14433. PMID: 28195122, PMCID: PMC5316884, DOI: 10.1038/ncomms14433.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesBrain NeoplasmsCell Transformation, NeoplasticChromosomal InstabilityCluster AnalysisDNA MethylationE2F2 Transcription FactorEnhancer of Zeste Homolog 2 ProteinEpigenomicsExomeForkhead Box Protein M1Gene Expression ProfilingGene Expression Regulation, NeoplasticGene Regulatory NetworksGene SilencingGenes, Neurofibromatosis 2GenomeGenomicsGenotyping TechniquesHuman Embryonic Stem CellsHumansJumonji Domain-Containing Histone DemethylasesMeningeal NeoplasmsMeningiomaMolecular Probe TechniquesMutationPhenotypePolycomb Repressive Complex 2Promoter Regions, GeneticRNA, MessengerSequence AnalysisSignal TransductionSMARCB1 ProteinTranscriptomeConceptsPolycomb repressive complex 2Human embryonic stem cellsRepressive complex 2Integrated genomic analysisEmbryonic stem cellsDe novo pathwayH3K27me3 signalsTranscriptional networksPRC2 complexEpigenomic analysisCellular statesCatalytic subunitGenomic analysisGenomic instabilityHypermethylated phenotypeGenomic landscapeNovo pathwayDisplay lossStem cellsPotential therapeutic targetExhibit upregulationPromoter mutationsTherapeutic targetMutationsComplexes 2Longitudinal 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
Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas
Clark VE, Harmancı AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, Ercan-Sencicek AG, Abraham BJ, Weintraub AS, Hnisz D, Simon M, Krischek B, Erson-Omay EZ, Henegariu O, Carrión-Grant G, Mishra-Gorur K, Durán D, Goldmann JE, Schramm J, Goldbrunner R, Piepmeier JM, Vortmeyer AO, Günel JM, Bilgüvar K, Yasuno K, Young RA, Günel M. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nature Genetics 2016, 48: 1253-1259. PMID: 27548314, PMCID: PMC5114141, DOI: 10.1038/ng.3651.Peer-Reviewed Original ResearchCatalytic DomainChromosomes, Human, Pair 22Cohort StudiesDNA Mutational AnalysisEnhancer Elements, GeneticExomeGene Expression Regulation, NeoplasticGenotypeHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMeningeal NeoplasmsMeningiomaMutationNeurofibromin 2RNA Polymerase IITumor Necrosis Factor Receptor-Associated Peptides and Proteins
2015
Integrated genomic characterization of IDH1-mutant glioma malignant progression
Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nature Genetics 2015, 48: 59-66. PMID: 26618343, PMCID: PMC4829945, DOI: 10.1038/ng.3457.Peer-Reviewed Original ResearchConceptsDevelopmental transcription factorsActivation of MYCMalignant progressionGenomic approachesPI3K pathwayGlioma malignant progressionEpigenetic silencingIDH1 mutant gliomasTranscription factorsIntegrated genomic characterizationGenomic characterizationRTK-RASOncogenic pathwaysK pathwayClonal expansionPathwaySilencingMYCProgressionWhole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Günel M, Bäckdahl M, Gimm O, Söderkvist P, Prasad ML, Korah R, Lifton RP, Carling T. Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes And Cancer 2015, 54: 542-554. PMID: 26032282, PMCID: PMC4755142, DOI: 10.1002/gcc.22267.Peer-Reviewed Original ResearchSomatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
Erson-Omay EZ, Çağlayan AO, Schultz N, Weinhold N, Omay SB, Özduman K, Köksal Y, Li J, Serin Harmancı A, Clark V, Carrión-Grant G, Baranoski J, Çağlar C, Barak T, Coşkun S, Baran B, Köse D, Sun J, Bakırcıoğlu M, Moliterno Günel J, Pamir MN, Mishra-Gorur K, Bilguvar K, Yasuno K, Vortmeyer A, Huttner AJ, Sander C, Günel M. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro-Oncology 2015, 17: 1356-1364. PMID: 25740784, PMCID: PMC4578578, DOI: 10.1093/neuonc/nov027.Peer-Reviewed Original ResearchConceptsHigh-grade gliomasSomatic POLE mutationsPOLE mutationsMalignant high-grade gliomasLonger progression-free survivalProgression-free survivalSomatic mutationsOverall survivalPediatric patientsBetter prognosisClinical featuresImproved prognosisClinical behaviorImmune cellsBizarre cellsAggressive formGlioblastoma multiformeDisease pathophysiologyMolecular subgroupsHomozygous germline mutationGermline mutationsPrognosisGlioma subtypesComprehensive genomic analysisDistinct subgroups
2014
Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, C. N, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, Günel M. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors. Neuron 2014, 84: 1226-1239. PMID: 25521378, PMCID: PMC5024344, DOI: 10.1016/j.neuron.2014.12.014.Peer-Reviewed Original ResearchConceptsComplex cerebral malformationsCerebral cortical malformationsMicrotubule-severing enzyme kataninExome sequencing analysisMitotic spindle formationDrosophila optic lobeCerebral malformationsPatient-derived fibroblastsCell cycle progression delayCortical malformationsMotor neuronsComplex malformationsMicrotubule-associated proteinsCortical developmentReduced cell numberOptic lobeRegulatory subunitBrain developmentCatalytic subunitDeleterious mutationsSpindle formationSupernumerary centrosomesArborization defectsMalformationsHuman phenotypesBrain Malformations Associated With Knobloch Syndrome—Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations
Caglayan AO, Baranoski JF, Aktar F, Han W, Tuysuz B, Guzel A, Guclu B, Kaymakcalan H, Aktekin B, Akgumus GT, Murray PB, Erson-Omay EZ, Caglar C, Bakircioglu M, Sakalar YB, Guzel E, Demir N, Tuncer O, Senturk S, Ekici B, Minja FJ, Šestan N, Yasuno K, Bilguvar K, Caksen H, Gunel M. Brain Malformations Associated With Knobloch Syndrome—Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations. Pediatric Neurology 2014, 51: 806-813.e8. PMID: 25456301, PMCID: PMC5056964, DOI: 10.1016/j.pediatrneurol.2014.08.025.Peer-Reviewed Original ResearchConceptsBrain malformationsKnobloch syndromeCentral nervous system malformationsExpanding Clinical SpectrumStructural brain abnormalitiesStructural brain malformationsNervous system malformationsHuman cerebral cortexHuman cortical developmentWhole-exome sequencingConfirmatory Sanger sequencingCase seriesClinical presentationCerebral cortexClinical spectrumBrain abnormalitiesOcular abnormalitiesSystem malformationsClinical utilityCortical developmentImmunohistochemical analysisRare diseaseCOL18A1 mutationsBrain developmentPatientsPaediatric 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 childhood
2013
Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO
Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Özduman K, Avşar T, Li J, Murray PB, Henegariu O, Yilmaz S, Günel JM, Carrión-Grant G, Yılmaz B, Grady C, Tanrıkulu B, Bakırcıoğlu M, Kaymakçalan H, Caglayan AO, Sencar L, Ceyhun E, Atik AF, Bayri Y, Bai H, Kolb LE, Hebert RM, Omay SB, Mishra-Gorur K, Choi M, Overton JD, Holland EC, Mane S, State MW, Bilgüvar K, Baehring JM, Gutin PH, Piepmeier JM, Vortmeyer A, Brennan CW, Pamir MN, Kılıç T, Lifton RP, Noonan JP, Yasuno K, Günel M. Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO. Science 2013, 339: 1077-1080. PMID: 23348505, PMCID: PMC4808587, DOI: 10.1126/science.1233009.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBrain NeoplasmsChromosomes, Human, Pair 22DNA Mutational AnalysisFemaleGenes, Neurofibromatosis 2Genomic InstabilityGenomicsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMeningeal NeoplasmsMeningiomaMiddle AgedMutationNeoplasm GradingProto-Oncogene Proteins c-aktReceptors, G-Protein-CoupledSmoothened ReceptorTumor Necrosis Factor Receptor-Associated Peptides and Proteins
2011
Recessive LAMC3 mutations cause malformations of occipital cortical development
Barak T, Kwan KY, Louvi A, Demirbilek V, Saygı S, Tüysüz B, Choi M, Boyacı H, Doerschner K, Zhu Y, Kaymakçalan H, Yılmaz S, Bakırcıoğlu M, Çağlayan A, Öztürk A, Yasuno K, Brunken WJ, Atalar E, Yalçınkaya C, Dinçer A, Bronen RA, Mane S, Özçelik T, Lifton RP, Šestan N, Bilgüvar K, Günel M. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nature Genetics 2011, 43: 590-594. PMID: 21572413, PMCID: PMC3329933, DOI: 10.1038/ng.836.Peer-Reviewed Original Research
2010
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 mutationsPachygyriaPathogenesisHypoplasiaNeocortexNeurogenesisAbnormalitiesMalformationsMutations