2023
Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease
Mishra-Gorur K, Barak T, Kaulen L, Henegariu O, Jin S, Aguilera S, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, K. D, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek A, Bilguvar K, Lifton R, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, Gunel M. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2214997120. PMID: 37043537, PMCID: PMC10120005, DOI: 10.1073/pnas.2214997120.Peer-Reviewed Original ResearchConceptsWild-type proteinInherited mutationsCardiac outflow tractDevelopmental heart defectsProtein functionLack ciliaPleiotropic rolesMechanistic convergenceNeural crestCiliary defectsSomatic variantsForebrain meningesCommon originDominant mannerMutationsTRAF7ZebrafishMutantsDisparate pathologiesHeterodimerizationKnockdownGeneticsProteinCiliaCongenital heart
2022
Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes
Tuysuz B, Alkaya D, Geyik F, Alaylıoğlu M, Kasap B, Kurugoğlu S, Akman Y, Vural M, Bilguvar K. Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes. Journal Of Medical Genetics 2022, 60: 819-826. PMID: 36543534, DOI: 10.1136/jmg-2022-108763.Peer-Reviewed Original ResearchConceptsOsteogenesis imperfectaWestern blot analysisPathogenic variantsFrameshift variantSkin fibroblast samplesExpression levelsInsulin-dependent Akt phosphorylationBlot analysisAutosomal recessive osteogenesis imperfectaWhole-exome sequencingMRNA expression levelsType 1 collagenBisphosphonate treatmentRecurrent fracturesClinical evaluationRecessive osteogenesis imperfectaCommon findingReal-time PCRMRNA expressionVertebral changesHeterogeneous groupAkt phosphorylationLong bonesBloodSkin fibroblastsMutation 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 patientsBiallelic BICD2 variant is a novel candidate for Cohen-like syndrome
Caglayan AO, Tuysuz B, Gül E, Alkaya DU, Yalcinkaya C, Gleeson JG, Bilguvar K, Gunel M. Biallelic BICD2 variant is a novel candidate for Cohen-like syndrome. Journal Of Human Genetics 2022, 67: 553-556. PMID: 35338243, PMCID: PMC9420744, DOI: 10.1038/s10038-022-01032-1.Peer-Reviewed Original ResearchConceptsWhole-exome sequencing analysisTruncal obesityJoint hypermobilityLower extremitiesHomozygous missense mutationSevere formBICD2 mutationsType 2BHeterozygous mutationsSpeech delayType 2AIntellectual disabilityPatientsSyndromeConsanguineous unionsMissense mutationsNovel candidatesSequencing analysisFirst reportMutations
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 ruptureVariantsBiallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
Wiessner M, Maroofian R, Ni MY, Pedroni A, Müller JS, Stucka R, Beetz C, Efthymiou S, Santorelli FM, Alfares AA, Zhu C, Meszarosova A, Alehabib E, Bakhtiari S, Janecke AR, Otero MG, Chen JYH, Peterson JT, Strom TM, De Jonghe P, Deconinck T, De Ridder W, De Winter J, Pasquariello R, Ricca I, Alfadhel M, van de Warrenburg BP, Portier R, Bergmann C, Firouzabadi S, Jin SC, Bilguvar K, Hamed S, Abdelhameed M, Haridy NA, Maqbool S, Rahman F, Anwar N, Carmichael J, Pagnamenta A, Wood NW, Mau-Them F, Haack T, Consortium P, Di Rocco M, Ceccherini I, Iacomino M, Zara F, Salpietro V, Scala M, Rusmini M, Xu Y, Wang Y, Suzuki Y, Koh K, Nan H, Ishiura H, Tsuji S, Lambert L, Schmitt E, Lacaze E, Küpper H, Dredge D, Skraban C, Goldstein A, Willis M, Grand K, Graham J, Lewis R, Millan F, Duman Ö, Dündar N, Uyanik G, Schöls L, Nürnberg P, Nürnberg G, Bordes A, Seeman P, Kuchar M, Darvish H, Rebelo A, Bouçanova F, Medard J, Chrast R, Auer-Grumbach M, Alkuraya F, Shamseldin H, Al Tala S, Varaghchi J, Najafi M, Deschner S, Gläser D, Hüttel W, Kruer M, Kamsteeg E, Takiyama Y, Züchner S, Baets J, Synofzik M, Schüle R, Horvath R, Houlden H, Bartesaghi L, Lee H, Ampatzis K, Pierson T, Senderek J. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain 2021, 144: 1422-1434. PMID: 33970200, PMCID: PMC8219359, DOI: 10.1093/brain/awab041.Peer-Reviewed Original ResearchConceptsHereditary spastic paraplegiaPure hereditary spastic paraplegiaGlobal developmental delaySpastic paraplegiaNervous systemNeurological diseasesComplicated hereditary spastic paraplegiaDevelopmental delayAbnormal motor behaviorRespiratory decompensationSpastic tetraplegiaNeurological manifestationsTruncating changesMissense substitutionsBiallelic variantsParaplegiaMotor behaviorDiseaseNeural differentiationUnknown specificityHuman diseasesMitochondrial diseaseDecompensationSpasticityTetraplegiaResolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl
Alkaya D, Akpınar E, Bilguvar K, Tüysüz B. Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl. American Journal Of Medical Genetics Part A 2021, 185: 2271-2277. PMID: 33837634, DOI: 10.1002/ajmg.a.62198.Peer-Reviewed Original ResearchConceptsCortical thickeningShort statureThree-year-old girlLarge anterior fontanelleLong bone metaphysisDiffuse sclerosisFracture historyElbow contractureAnterior fontanelleSclerotic lesionsBone fragilitySpontaneous resolutionBone metaphysisMild sclerosisSkeletal radiographsSclerosisMelanocytic neviBone dysplasiaSkull baseHeterogeneous disorderSLC29A3 mutationsVertebral endplatesBiallelic mutationsTurkish girlPelvic bonesIntegrated mutational landscape analysis of uterine leiomyosarcomas
Choi J, Manzano A, Dong W, Bellone S, Bonazzoli E, Zammataro L, Yao X, Deshpande A, Zaidi S, Guglielmi A, Gnutti B, Nagarkatti N, Tymon-Rosario JR, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Jeong K, Zhao S, Buza N, Hui P, Ravaggi A, Bignotti E, Romani C, Todeschini P, Zanotti L, Odicino F, Pecorelli S, Ardighieri L, Bilguvar K, Quick CM, Silasi DA, Huang GS, Andikyan V, Clark M, Ratner E, Azodi M, Imielinski M, Schwartz PE, Alexandrov LB, Lifton RP, Schlessinger J, Santin AD. Integrated mutational landscape analysis of uterine leiomyosarcomas. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2025182118. PMID: 33876771, PMCID: PMC8053980, DOI: 10.1073/pnas.2025182118.Peer-Reviewed Original ResearchConceptsHomologous recombination DNA repair deficiencySequencing dataWhole-genome sequencing dataRNA sequencing dataTCGA samplesCopy number variation analysisATRX/DAXXCopy number lossNumber variation analysisDNA repair deficiencyWhole-exome sequencing dataRecurrent somatic mutationsCopy number gainsCancer Genome AtlasPatient-derived xenograftsTumor suppressorAkt geneGenetic landscapeHRD signaturesPTEN geneGenesMost fusionsC-MycMutational signaturesC-myc/
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 typesMutations disrupting neuritogenesis genes confer risk for cerebral palsy
Jin SC, Lewis SA, Bakhtiari S, Zeng X, Sierant MC, Shetty S, Nordlie SM, Elie A, Corbett MA, Norton BY, van Eyk CL, Haider S, Guida BS, Magee H, Liu J, Pastore S, Vincent JB, Brunstrom-Hernandez J, Papavasileiou A, Fahey MC, Berry JG, Harper K, Zhou C, Zhang J, Li B, Zhao H, Heim J, Webber DL, Frank MSB, Xia L, Xu Y, Zhu D, Zhang B, Sheth AH, Knight JR, Castaldi C, Tikhonova IR, López-Giráldez F, Keren B, Whalen S, Buratti J, Doummar D, Cho M, Retterer K, Millan F, Wang Y, Waugh JL, Rodan L, Cohen JS, Fatemi A, Lin AE, Phillips JP, Feyma T, MacLennan SC, Vaughan S, Crompton KE, Reid SM, Reddihough DS, Shang Q, Gao C, Novak I, Badawi N, Wilson YA, McIntyre SJ, Mane SM, Wang X, Amor DJ, Zarnescu DC, Lu Q, Xing Q, Zhu C, Bilguvar K, Padilla-Lopez S, Lifton RP, Gecz J, MacLennan AH, Kruer MC. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nature Genetics 2020, 52: 1046-1056. PMID: 32989326, PMCID: PMC9148538, DOI: 10.1038/s41588-020-0695-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBeta CateninCerebral PalsyCyclin DCytoskeletonDrosophilaExomeExome SequencingExtracellular MatrixF-Box ProteinsFemaleFocal AdhesionsGenetic Predisposition to DiseaseGenome, HumanHumansMaleMutationNeuritesRhoB GTP-Binding ProteinRisk FactorsSequence Analysis, DNASignal TransductionTubulinTumor Suppressor ProteinsConceptsDamaging de novo mutationsCerebral palsyDe novo mutationsCerebral palsy casesRisk genesDamaging de novoNovo mutationsWhole-exome sequencingPalsy casesNeuromotor functionD levelsMonogenic etiologyCyclin D levelsNeuronal connectivityPalsyGene confer riskConfer riskRecessive variantsNeurodevelopmental disorder genesReverse genetic screenDisorder genesParent-offspring triosGenome-wide significanceGenomic factorsCytoskeleton pathwayMETAP1 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 diseasePathwayCellsHuman CRY1 variants associate with attention deficit/hyperactivity disorder
Onat OE, Kars ME, Gül Ş, Bilguvar K, Wu Y, Özhan A, Aydın C, Başak AN, Trusso MA, Goracci A, Fallerini C, Renieri A, Casanova JL, Itan Y, Atbaşoğlu CE, Saka MC, Kavaklı İ, Özçelik T. Human CRY1 variants associate with attention deficit/hyperactivity disorder. Journal Of Clinical Investigation 2020, 130: 3885-3900. PMID: 32538895, PMCID: PMC7324179, DOI: 10.1172/jci135500.Peer-Reviewed Original ResearchConceptsAttention-deficit/hyperactivity disorderDeficit/hyperactivity disorderHyperactivity disorderMajor depressive disorderSleep phase disorderGenotype-phenotype correlation analysisAdult EuropeansDepressive disorderIndependent cohortTherapeutic markersFunctional alterationsBehavioral symptomsInsomniaExome sequencingPhenome-wide association studyDisordersPhase disorderPatientsPsychiatric phenotypesMechanistic linkAffected familyArrhythmic phenotypeMolecular rhythmsPhenotypeAnxietyBi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
Chatron N, Becker F, Morsy H, Schmidts M, Hardies K, Tuysuz B, Roselli S, Najafi M, Alkaya DU, Ashrafzadeh F, Nabil A, Omar T, Maroofian R, Karimiani EG, Hussien H, Kok F, Ramos L, Gunes N, Bilguvar K, Labalme A, Alix E, Sanlaville D, de Bellescize J, Poulat AL, Helbig I, von Spiczak S, Baulac S, Barisic N, Balling R, Caglayan H, Craiu D, Guerrini R, Klein K, Marini C, Muhle H, Rosenow F, Serratosa J, Sterbova K, Weber Y, Moslemi A, Lerche H, May P, Lesca G, Weckhuysen S, Tajsharghi H. Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy. Brain 2020, 143: 1447-1461. PMID: 32282878, PMCID: PMC7241960, DOI: 10.1093/brain/awaa085.Peer-Reviewed Original ResearchConceptsEpileptic encephalopathyJoint contracturesSeizure onsetCleft palateMonths of lifePost-neonatal periodYears of ageBi-allelic lossΓ-aminobutyric acid (GABA) metabolismEnzyme GAD67Epileptic spasmsEarly EEGEpilepsy syndromesMyoclonic seizuresEarly-onset epilepsy syndromeDisease historyPes equinovarusPatientsNovel syndromeEncephalopathyBurst attenuationIndependent consanguineous familiesFirst monthTherapeutic hopeFunction variants
2019
Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy
Zammataro L, Lopez S, Bellone S, Pettinella F, Bonazzoli E, Perrone E, Zhao S, Menderes G, Altwerger G, Han C, Zeybek B, Bianchi A, Manzano A, Manara P, Cocco E, Buza N, Hui P, Wong S, Ravaggi A, Bignotti E, Romani C, Todeschini P, Zanotti L, Odicino F, Pecorelli S, Donzelli C, Ardighieri L, Angioli R, Raspagliesi F, Scambia G, Choi J, Dong W, Bilguvar K, Alexandrov LB, Silasi DA, Huang GS, Ratner E, Azodi M, Schwartz PE, Pirazzoli V, Stiegler AL, Boggon TJ, Lifton RP, Schlessinger J, Santin AD. Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 22730-22736. PMID: 31624127, PMCID: PMC6842590, DOI: 10.1073/pnas.1911385116.Peer-Reviewed Original ResearchConceptsPI3K/AKT/mTOR pathwaySquamous cell carcinomaWhole-exome sequencingAKT/mTOR pathwayPrimary cervical cancer cell linesPIK3CA inhibitorsRecurrent cervical cancer patientsMTOR pathwayCombination of copanlisibCervical cancer patientsPI3K/Akt/mTORCervical cancer xenograftsRegression of tumorsCervical cancer cell linesCervical tumor cell linesSingle nucleotide variantsWild-type tumorsRecurrent somatic missense mutationsAkt/mTORCell linesPan-HERCancer cell linesTypes 16/18Cervical cancerCancer patientsIdentification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing
Dong W, Baldwin C, Choi J, Milunsky JM, Zhang J, Bilguvar K, Lifton RP, Milunsky A. Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing. Clinical Genetics 2019, 96: 473-477. PMID: 31389005, DOI: 10.1111/cge.13617.Peer-Reviewed Original ResearchConceptsChronic Intestinal Pseudo-ObstructionSmooth muscle actin geneMuscle actin geneAdditional genetic evidenceGene burden analysisIntestinal Pseudo-ObstructionRare gastrointestinal disorderSmooth muscle contractionActin geneMyosin genesAdditional genesGenetic evidenceCausal variantsWhole-exome sequencingFamily membersCIPO patientsPseudo-ObstructionGenetic linkageGastrointestinal disordersDominant mutationsGenesUnaffected family membersGastrointestinal tractRare mutationsMuscle contractionMutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis
Timberlake AT, Jin SC, Nelson-Williams C, Wu R, Furey CG, Islam B, Haider S, Loring E, Galm A, Steinbacher D, Larysz D, Staffenberg D, Flores R, Rodriguez E, Boggon T, Persing J, Lifton R, Lifton RP, Gunel M, Mane S, Bilguvar K, Gerstein M, Loring E, Nelson-Williams C, Lopez F, Knight J. Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 15116-15121. PMID: 31292255, PMCID: PMC6660739, DOI: 10.1073/pnas.1902041116.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAlpha CateninChildChild, PreschoolCraniosynostosesExomeExome SequencingFemaleGene ExpressionGlypicansHistone AcetyltransferasesHumansMaleMutationNuclear ProteinsPedigreeRisk AssessmentSignal TransductionSkullSOXC Transcription FactorsTranscription Factor AP-2Zinc Finger Protein Gli2ConceptsRare damaging mutationsSyndromic craniosynostosisCongenital anomaliesDamaging mutationsSyndromic casesExome sequencingAdditional congenital anomaliesFrequent congenital anomaliesDamaging de novo mutationsNeural crest cell migrationDamaging de novoCrest cell migrationCS patientsMutation burdenChromatin modifiersSubsequent childrenTranscription factorsDe novo mutationsCS casesCS geneHedgehog pathwayDisease locusPremature fusionFunction mutationsCraniosynostosis
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 implicationsLoss 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 expressionBiallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration
Schaffer AE, Breuss MW, Caglayan AO, Al-Sanaa N, Al-Abdulwahed HY, Kaymakçalan H, Yılmaz C, Zaki MS, Rosti RO, Copeland B, Baek ST, Musaev D, Scott EC, Ben-Omran T, Kariminejad A, Kayserili H, Mojahedi F, Kara M, Cai N, Silhavy JL, Elsharif S, Fenercioglu E, Barshop BA, Kara B, Wang R, Stanley V, James KN, Nachnani R, Kalur A, Megahed H, Incecik F, Danda S, Alanay Y, Faqeih E, Melikishvili G, Mansour L, Miller I, Sukhudyan B, Chelly J, Dobyns WB, Bilguvar K, Jamra RA, Gunel M, Gleeson JG. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. Nature Genetics 2018, 50: 1093-1101. PMID: 30013181, PMCID: PMC6072555, DOI: 10.1038/s41588-018-0166-0.Peer-Reviewed Original ResearchConceptsNeuronal migrationHuman cerebral cortexCortical neuronal migrationΒ-catenin signalingCerebral cortexPotential disease mechanismsDevelopmental brain defectsBiallelic truncating mutationsNeuronal phenotypeBiallelic lossBrain defectsBiallelic mutationsTruncating mutationsDisease mechanismsΒ-cateninPachygyriaRecessive formNeurite stabilityNeuronsFamily membersCTNNA2OveractivityPatientsDe Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus
Furey CG, Choi J, Jin SC, Zeng X, Timberlake AT, Nelson-Williams C, Mansuri MS, Lu Q, Duran D, Panchagnula S, Allocco A, Karimy JK, Khanna A, Gaillard JR, DeSpenza T, Antwi P, Loring E, Butler WE, Smith ER, Warf BC, Strahle JM, Limbrick DD, Storm PB, Heuer G, Jackson EM, Iskandar BJ, Johnston JM, Tikhonova I, Castaldi C, López-Giráldez F, Bjornson RD, Knight JR, Bilguvar K, Mane S, Alper SL, Haider S, Guclu B, Bayri Y, Sahin Y, Apuzzo MLJ, Duncan CC, DiLuna ML, Günel M, Lifton RP, Kahle KT. De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. Neuron 2018, 99: 302-314.e4. PMID: 29983323, PMCID: PMC7839075, DOI: 10.1016/j.neuron.2018.06.019.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusNeural stem cell fateHuman congenital hydrocephalusDamaging de novoCerebrospinal fluid homeostasisSubstantial morbidityCH patientsTherapeutic ramificationsSignificant burdenBrain ventriclesCH pathogenesisNeural tube developmentFluid homeostasisDe novo mutationsExome sequencingAdditional probandsHydrocephalusPathogenesisNovo mutationsNovo duplicationProbandsDe novoCell fateMorbidityPatients