2023
169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation
Mekbib K, Zhao S, Nelson-Williams C, Prendergast A, Zeng X, Rolle M, Shohfi J, Smith H, Ocken J, Moyer Q, Piwowarczyk P, Allington G, Dong W, van der Ent M, Chen D, Li B, Duran D, Mane S, Walcott B, Stapleton C, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith E, Orbach D, Berenstein A, Bilguvar K, Zhao H, Erson-Omay Z, King P, Huttner A, Lifton R, Boggon T, Nicoli S, Jin S, Kahle K. 169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation. Neurosurgery 2023, 69: 22-22. DOI: 10.1227/neu.0000000000002375_169.Peer-Reviewed Original ResearchPathway analysisP120 Ras-GAPExome sequencingSevere vascular defectsGalen aneurysmal malformationReceptor tyrosine kinase activityTyrosine kinase activityDamaging de novoMutant embryosRas-GAPSignaling networksGenetic regulationRas activationAneurysmal malformationZebrafish modelDe novo mutationsKinase activityDisease genesAxon guidanceGenetic samplesWhole-exome sequencingHigh-output heart failureFunctional studiesCollected specimensSequencing
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 pathway
2019
Mutations 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
De 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
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-3De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis
Timberlake AT, Furey CG, Choi J, Nelson-Williams C, Loring E, Galm A, Kahle K, Steinbacher D, Larysz D, Persing J, Lifton R, Bilguvar K, Mane S, Tikhonova I, Castaldi C, Knight J. De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e7341-e7347. PMID: 28808027, PMCID: PMC5584457, DOI: 10.1073/pnas.1709255114.Peer-Reviewed Original ResearchConceptsBone morphogenetic proteinRas/ERKDe novo mutationsNovo mutationsRas/ERK pathwayDamaging de novo mutationsHigh locus heterogeneityRare syndromic diseaseCommon risk variantsInhibitor of WntSyndromic craniosynostosesNew genesParent-offspring triosSyndromic diseaseMorphogenetic proteinsNegative regulatorERK pathwayMore cranial suturesGenesMidline craniosynostosisRisk variantsWntLocus heterogeneityMutationsExome sequencing
2016
A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia
Smedemark-Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, Gonzalez-Cuevas E, Liu KX, Bilguvar K, Kleiman RJ, Han MJ, Torres A, Berry GT, Yu TW, Beggs AH, Agrawal PB, Gonzalez-Heydrich J. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Molecular Case Studies 2016, 2: a001008. PMID: 27626066, PMCID: PMC5002930, DOI: 10.1101/mcs.a001008.Peer-Reviewed Original ResearchRapid-onset dystonia-parkinsonismCommand auditory hallucinationsNovel clinical presentationHemiplegia of childhoodChildhood-onset schizophreniaNovel de novo mutationYr of ageMild motor delayWhole-exome sequencingChromosomal microarray analysisNeuron-specific isoformSodium-potassium pumpClinical presentationDystonia-parkinsonismBehavioral regressionAuditory hallucinationsMotor delayNeuronal functionDe novo mutationsHeterozygous mutationsMutation c.ATP1A3Novo mutationsMicroarray analysisPast functional studies
2015
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies
Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA, Kim R, Bilguvar K, López-Giráldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WK. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 2015, 350: 1262-1266. PMID: 26785492, PMCID: PMC4890146, DOI: 10.1126/science.aac9396.Peer-Reviewed Original ResearchConceptsCongenital anomaliesNeurodevelopmental disabilitiesCongenital heart disease patientsDe novo mutationsExtracardiac congenital anomaliesImproved prognostic assessmentEarly therapeutic interventionHeart disease patientsCongenital heart diseaseNovo mutationsCHD patientsDisease patientsHeart diseasePrognostic assessmentCHD casesTherapeutic interventionsPatientsExome sequencingCHDParent-offspring triosMultiple mutationsGenetic contributionMutationsChromatin modificationsTranscriptional regulation
2014
Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia
Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, Lifton RP, Bilguvar K, , Paller A, Choate K. Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia. Journal Of Investigative Dermatology 2014, 135: 1540-1547. PMID: 25398053, PMCID: PMC4430428, DOI: 10.1038/jid.2014.485.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCell MembraneChildChild, PreschoolConnexin 43ConnexinsCraniofacial AbnormalitiesDisease ProgressionErythrokeratodermia VariabilisExomeEye AbnormalitiesFemaleFoot Deformities, CongenitalGolgi ApparatusHeLa CellsHumansImmunohistochemistryMaleMolecular Sequence DataMutagenesis, Site-DirectedMutationPhenotypeSequence Analysis, DNASequence Homology, Amino AcidSkin DiseasesSyndactylyTooth AbnormalitiesConceptsSkin diseasesGJA1 mutationsErythrokeratodermia variabilis et progressivaOculodentodigital dysplasiaProgressive skin diseaseDe novo missense mutationsNovo missense mutationCutaneous findingsDominant de novo mutationsSkin disordersGap junction proteinDe novo mutationsBarrier functionConnexin 43Exome sequencingJunction proteinsPalmoplantar keratodermaDysplasiaGJA1Novo mutationsDiseaseMissense mutationsDifferent mutationsEpidermal homeostasisMembrane localization