2024
Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes
Lu X, Ni P, Suarez-Meade P, Ma Y, Forrest E, Wang G, Wang Y, Quiñones-Hinojosa A, Gerstein M, Jiang Y. Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes. Cell Reports 2024, 43: 114376. PMID: 38900637, PMCID: PMC11328446, DOI: 10.1016/j.celrep.2024.114376.Peer-Reviewed Original ResearchSHANK family genesFamily genesLong-read sequencingCDNA captureTranscript structureDeleterious variantsGenomic studiesAbundant mRNAsTranscriptional dysregulationStochastic transcriptionStudies of neuropsychiatric disordersCausative genesTranscriptional profilesTranscriptional determinantsTranscriptomePostmortem brain tissueAutism spectrum disorderShank3 transcriptsTranscriptionGenesGenomeSHANK3Neuropsychiatric disordersSpectrum disorderAutism modelNovel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders
Lu X, Ng K, Pinto e Vairo F, Collins J, Cohn R, Riley K, Agre K, Gavrilova R, Klee E, Rosenfeld J, Jiang Y. Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders. European Journal Of Human Genetics 2024, 32: 879-883. PMID: 38702431, PMCID: PMC11219747, DOI: 10.1038/s41431-024-01576-0.Peer-Reviewed Original ResearchProtein-truncating variantsSyndromic neurodevelopmental disorderGenomic studiesChromatin-modifying enzymesAcetylation of histone H4Neurodevelopmental disordersLysine 34Histone 2BMono-ubiquitinationLysine 16Epigenetic machineryGenomic evaluationMSL2Exome sequencingHistone H4Epigenetic regulationModifying enzymesEpigenetic genesFunctional importanceGenesChromatinLysineDevelopmental disordersDysmorphic faceVariantsImpaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs
Zhu F, Shi Q, Jiang Y, Zhang Y, Zhao H. Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs. Molecular Autism 2024, 15: 9. PMID: 38297387, PMCID: PMC10829216, DOI: 10.1186/s13229-024-00587-4.Peer-Reviewed Original ResearchConceptsPrefrontal cortexPyramidal neuronsSHANK3 mutationsPrefrontal cortex neuronal activityPrefrontal cortex pyramidal neuronsSocial behaviorBrain slicesPrefrontal cortex's roleSynaptic transmissionPrefrontal cortex layersStudy social cognitionAutism spectrum disorderAutism-like behaviorsDendritic spine morphologyReduced dendritic complexitySocial cognitionSocial impairmentBehavioral alterationsNeural mechanismsExcitatory synaptic transmissionMutant rodent modelsHeightened anxietySpectrum disorderSpine densityImpaired synaptic functionPatterns of Cytogenomic Findings from a Case Series of Recurrent Pregnancy Loss Provide Insight into the Extent of Genetic Defects Causing Miscarriages
DiAdamo A, Chai H, Chong M, Wang G, Wen J, Jiang Y, Li P. Patterns of Cytogenomic Findings from a Case Series of Recurrent Pregnancy Loss Provide Insight into the Extent of Genetic Defects Causing Miscarriages. Global Medical Genetics 2024, 11: 123-131. PMID: 38560483, PMCID: PMC10980555, DOI: 10.1055/s-0044-1785227.Peer-Reviewed Original ResearchRecurrent pregnancy lossProducts of conceptionAbnormal karyotypeConsecutive miscarriagesCase seriesCytogenomic abnormalitiesCA groupCytogenomic findingsRoutine cytogenetic analysisCopy number variantsMonosomy XNormal karyotypeRetrospective studyPregnancy lossCytogenetic analysisPathogenic variantsMiscarriageSA groupAneuploidyKaryotypeLethal variantWomenAbnormalitiesGenome sequenceAbstract Background
2023
Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing
Tian R, Li Y, Zhao H, Lyu W, Zhao J, Wang X, Lu H, Xu H, Ren W, Tan Q, Shi Q, Wang G, Zhang Y, Lai L, Mi J, Jiang Y, Zhang Y. Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing. Molecular Psychiatry 2023, 28: 3739-3750. PMID: 37848710, DOI: 10.1038/s41380-023-02276-9.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderSpectrum disorderNon-human primatesDog-human social interactionsPreclinical studiesBattery of behavioral assaysSocial behavior deficitsASD mouse modelsSocial interactionReduced social interactionCRISPR/Cas9 gene editingGenetic mutant miceNeural circuit mechanismsSocial withdrawalBehavioral findingsPsychiatric disordersBehavioral deficitsHeightened anxietyCanine modelSHANK3 mutationsSHANK3 geneCircuit mechanismsMutant miceMouse modelBehavioral assays
2022
Vitamin C epigenetically controls osteogenesis and bone mineralization
Thaler R, Khani F, Sturmlechner I, Dehghani SS, Denbeigh JM, Zhou X, Pichurin O, Dudakovic A, Jerez SS, Zhong J, Lee JH, Natarajan R, Kalajzic I, Jiang YH, Deyle DR, Paschalis EP, Misof BM, Ordog T, van Wijnen AJ. Vitamin C epigenetically controls osteogenesis and bone mineralization. Nature Communications 2022, 13: 5883. PMID: 36202795, PMCID: PMC9537512, DOI: 10.1038/s41467-022-32915-8.Peer-Reviewed Original ResearchConceptsSevere skeletal defectsBone-specific genesEpigenetic functionsChromatin accessibilityHistone demethylationDNA hydroxymethylationTranscriptional activityPro-osteogenic genesCell differentiationOsteogenic cell differentiationOsteogenic differentiationGenesSkeletal defectsBone phenotypeMurine boneOsteoblastogenesisDifferentiationKnockout miceGulo knockout miceVitamin C deficiencyTET1Collagen maturationPromoterDemethylationVitamin CA retrospective cohort analysis of the Yale pediatric genomics discovery program
Al‐Ali S, Jeffries L, Faustino EVS, Ji W, Mis E, Konstantino M, Zerillo C, Jiang Y, Spencer‐Manzon M, Bale A, Zhang H, McGlynn J, McGrath JM, Tremblay T, Brodsky NN, Lucas CL, Pierce R, Deniz E, Khokha MK, Lakhani SA. A retrospective cohort analysis of the Yale pediatric genomics discovery program. American Journal Of Medical Genetics Part A 2022, 188: 2869-2878. PMID: 35899841, PMCID: PMC9474639, DOI: 10.1002/ajmg.a.62918.Peer-Reviewed Original ResearchConceptsRetrospective cohort analysisNext-generation sequencingCohort analysisSystem abnormalitiesImmune system abnormalitiesCardiovascular system abnormalitiesFunctional molecular analysesNovel genesPrecise molecular diagnosisClinical characteristicsFurther genetic evaluationDiscovery programsComplex patientsMultisystem diseaseDisease genesPediatric providersRare genetic diseaseNew diagnosisPhenotype relationshipsPatientsGenetic diseasesMolecular analysisDiagnosisParticipant demographicsNGS resultsDisrupted Topological Organization of White Matter Network in Angelman Syndrome
Wei L, Du X, Yang Z, Ding M, Yang B, Wang J, Long S, Qiao Z, Jiang Y, Wang Y, Wang H. Disrupted Topological Organization of White Matter Network in Angelman Syndrome. Journal Of Magnetic Resonance Imaging 2022, 57: 1212-1221. PMID: 35856797, DOI: 10.1002/jmri.28360.Peer-Reviewed Original ResearchComparative Proteome and Cis-Regulatory Element Analysis Reveals Specific Molecular Pathways Conserved in Dog and Human Brains
Hong H, Zhao Z, Huang X, Guo C, Zhao H, Wang GD, Zhang YP, Zhao JP, Shi J, Wu QF, Jiang YH, Wang Y, Li LM, Du Z, Zhang YQ, Xiong Y. Comparative Proteome and Cis-Regulatory Element Analysis Reveals Specific Molecular Pathways Conserved in Dog and Human Brains. Molecular & Cellular Proteomics 2022, 21: 100261. PMID: 35738554, PMCID: PMC9304787, DOI: 10.1016/j.mcpro.2022.100261.Peer-Reviewed Original ResearchNeural circuit pathology driven by Shank3 mutation disrupts social behaviors
Kim S, Kim YE, Song I, Ujihara Y, Kim N, Jiang YH, Yin HH, Lee TH, Kim IH. Neural circuit pathology driven by Shank3 mutation disrupts social behaviors. Cell Reports 2022, 39: 110906. PMID: 35675770, PMCID: PMC9210496, DOI: 10.1016/j.celrep.2022.110906.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderAlters spine morphologyWild-type miceExcitatory-inhibitory balanceSocial dysfunctionHuman ASD patientsMultiple brain regionsSocial behaviorElevated neural activityCircuit pathologyPathogenic mechanismsSHANK3 mutationsCircuit inhibitionBrain regionsCircuit activationNeural network mechanismReduced sociabilitySpine morphologyCore symptomsASD patientsPrefrontal cortexMiceSHANK3 geneNeural activitySpectrum disorderEpigenetic Epidemiology of Autism and Other Neurodevelopmental Disorders
Wang S, Jiang Y. Epigenetic Epidemiology of Autism and Other Neurodevelopmental Disorders. 2022, 405-426. DOI: 10.1007/978-3-030-94475-9_17.ChaptersEpigenome-wide association studiesAbnormal DNA methylationDNA methylationHistone modificationsTissue-specific patternsNeurodevelopmental disordersEpigenetic regulationEpigenetic epidemiologyEmbryonic developmentEpigenetic dysregulationGenetic lociEpigenetic reprogramingAssociation studiesMethylationRecent technical advancesEnvironmental factorsRegion analysisEpimutationsReprogramingEtiology of NDDIntellectual disabilityLociTechnical advancesAllelesRegulationThe microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder
Barish S, Senturk M, Schoch K, Minogue AL, Lopergolo D, Fallerini C, Harland J, Seemann JH, Stong N, Kranz PG, Kansagra S, Mikati MA, Jasien J, El-Dairi M, Galluzzi P, Acosta M, Adam M, Adams D, Agrawal P, Alejandro M, Alvey J, Amendola L, Andrews A, Ashley E, Azamian M, Bacino C, Bademci G, Baker E, Balasubramanyam A, Baldridge D, Bale J, Bamshad M, Barbouth D, Bayrak-Toydemir P, Beck A, Beggs A, Behrens E, Bejerano G, Bennet J, Berg-Rood B, Bernstein J, Berry G, Bican A, Bivona S, Blue E, Bohnsack J, Bonnenmann C, Bonner D, Botto L, Boyd B, Briere L, Brokamp E, Brown G, Burke E, Burrage L, Butte M, Byers P, Byrd W, Carey J, Carrasquillo O, Chang T, Chanprasert S, Chao H, Clark G, Coakley T, Cobban L, Cogan J, Coggins M, Cole F, Colley H, Cooper C, Cope H, Craigen W, Crouse A, Cunningham M, D'Souza P, Dai H, Dasari S, Davids M, Dayal J, Deardorff M, Dell'Angelica E, Dhar S, Dipple K, Doherty D, Dorrani N, Douine E, Draper D, Duncan L, Earl D, Eckstein D, Emrick L, Eng C, Esteves C, Estwick T, Falk M, Fernandez L, Ferreira C, Fieg E, Findley L, Fisher P, Fogel B, Forghani I, Fresard L, GahlIan-Glass W, Godfrey R, Golden-Grant K, Goldman A, Goldstein D, Grajewski A, Groden C, Gropman A, Gutierrez I, Hahn S, Hamid R, Hanchard N, Hassey K, Hayes N, High F, Hing A, Hisama F, Holm I, Hom J, Horike-Pyne M, Huang A, Huang Y, Isasi R, Jamal F, Jarvik G, Jarvik J, Jayadev S, Johnston J, Karaviti L, Kelley E, Kennedy J, Kiley D, Kohane I, Kohler J, Krakow D, Krasnewich D, Kravets E, Korrick S, Koziura M, Krier J, Lalani S, Lam B, Lam C, Lanpher B, Lanza I, Lau C, LeBlanc K, Lee B, Lee H, Levitt R, Lewis R, Lincoln S, Liu P, Liu X, Longo N, Loo S, Loscalzo J, Maas R, Macnamara E, MacRae C, Maduro V, Majcherska M, Mak B, Malicdan M, Mamounas L, Manolio T, Mao R, Maravilla K, Markello T, Marom R, Marth G, Martin B, Martin M, Martínez-Agosto J, Marwaha S, McCauley J, McConkie-Rosell A, McCormack C, McCray A, McGee E, Mefford H, Merritt J, Might M, Mirzaa G, Morava E, Moretti P, Morimoto M, Mulvihill J, Murdock D, Nakano-Okuno M, Nath A, Nelson S, Newman J, Nicholas S, Nickerson D, Nieves-Rodriguez S, Novacic D, Oglesbee D, Orengo J, Pace L, Pak S, Pallais J, Palmer C, Papp J, Parker N, Phillips III J, Posey J, Potocki L, Pusey B, Quinlan A, Raskind W, Raja A, Rao D, Renteria G, Reuter C, Rives L, Robertson A, Rodan L, Rosenfeld J, Rosenwasser N, Ruzhnikov M, Sacco R, Sampson J, Samson S, Saporta M, Scott C, Schaechter J, Schedl T, Schoch K, Scott D, Sharma P, Shashi V, Shin J, Signer R, Sillari C, Silverman E, Sinsheimer J, Sisco K, Smith E, Smith K, Solem E, Solnica-Krezel L, Spillmann R, Stoler J, StongJ N, Sullivan E, Sullivan K, Sun A, Sutton S, Sweetser D, Sybert V, Tabor H, Tamburro C, K-GTan Q, Tekin M, Telischi F, Thorson W, Tifft C, Toro C, Tran A, Tucker B, Urv T, Vanderver A, Velinder M, Viskochil D, Vogel T, Wahl C, Wallace S, Walley N, Walsh C, Walker M, Wambach J, Wan J, Wang L, Wangler M, Ward P, Wegner D, Wener M, Wenger T, Perry K, Westerfield M, Wheeler M, Whitlock J, Wolfe L, Woods J, Yamamoto S, Yang J, Yu G, Zastrow D, Zhao C, Zuchner S, Ariani F, Renieri A, Mari F, Wangler M, Arur S, Jiang Y, Yamamoto S, Shashi V, Bellen H. The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder. Human Molecular Genetics 2022, 31: 2934-2950. PMID: 35405010, PMCID: PMC9433733, DOI: 10.1093/hmg/ddac085.Peer-Reviewed Original ResearchConceptsWhite matter atrophyProgressive neurological disorderDe novo heterozygous variantsNovo heterozygous variantsProfound intellectual disabilityMatter atrophyNervous systemNeurological disordersHeterozygous variantsDysmorphic featuresMissense variantsSevere phenotypeIntellectual disabilityPhenotype characteristicLoss of DroshaLoss of miRNAMiRNA expressionBrain sizeSevere reductionSevere progressive neurological disorderFunctional studiesCauses lossAtrophyEpilepsyCandidate genesBrain-wide electrical dynamics encode individual appetitive social behavior
Mague SD, Talbot A, Blount C, Walder-Christensen KK, Duffney LJ, Adamson E, Bey AL, Ndubuizu N, Thomas GE, Hughes DN, Grossman Y, Hultman R, Sinha S, Fink AM, Gallagher NM, Fisher RL, Jiang YH, Carlson DE, Dzirasa K. Brain-wide electrical dynamics encode individual appetitive social behavior. Neuron 2022, 110: 1728-1741.e7. PMID: 35294900, PMCID: PMC9126093, DOI: 10.1016/j.neuron.2022.02.016.Peer-Reviewed Original ResearchDetecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients
Wen J, Chai H, Grommisch B, DiAdamo A, Dykas D, Ma D, Popa A, Zhao C, Spencer‐Manzon M, Jiang Y, McGrath J, Li P, Bale A, Zhang H. Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients. American Journal Of Medical Genetics Part A 2022, 188: 1728-1738. PMID: 35199448, DOI: 10.1002/ajmg.a.62693.Peer-Reviewed Original ResearchConceptsPediatric patientsWhole-exome sequencingCase seriesAR diseasesPathogenic variantsLarge consecutive case seriesConsecutive case seriesLarge case seriesUniparental disomyLikely pathogenic variantsRegions of homozygosityChromosomal microarray analysisAutosomal recessive diseasePrader-Willi syndromeDiagnostic findingsDiagnostic yieldPatientsPredictive valueGenetic testingHomozygous variantDiseaseExome sequencingRecessive diseaseGenetic counselingStrongest predictorInhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism
Tzanoulinou S, Musardo S, Contestabile A, Bariselli S, Casarotto G, Magrinelli E, Jiang YH, Jabaudon D, Bellone C. Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism. Molecular Psychiatry 2022, 27: 2080-2094. PMID: 35022531, PMCID: PMC9126815, DOI: 10.1038/s41380-021-01427-0.Peer-Reviewed Original ResearchConceptsAcute inflammatory responseInflammatory responseSHANK3 geneTransient receptor potential vanilloid 4Shank3 mouse modelAutism spectrum disorderGenetic risk factorsInhibition of TRPV4Ex vivo approachNeuron hyperexcitabilityRisk factorsBehavioral deficitsNucleus accumbensMouse modelTRPV4 inhibitionBehavioral alterationsSocial deficitsSHANK3 mutationsCircuit mechanismsNeurodevelopmental diseasesGenetic alterationsTypes of mutationsHeterozygous deletionIdiopathic autismEnvironmental insultsStankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype.
Isidor B, Ebstein F, Hurst A, Vincent M, Bader I, Rudy NL, Cogne B, Mayr J, Brehm A, Bupp C, Warren K, Bacino CA, Gerard A, Ranells JD, Metcalfe KA, van Bever Y, Jiang YH, Mendelssohn BA, Cope H, Rosenfeld JA, Blackburn PR, Goodenberger ML, Kearney HM, Kennedy J, Scurr I, Szczaluba K, Ploski R, de Saint Martin A, Alembik Y, Piton A, Bruel AL, Thauvin-Robinet C, Strong A, Diderich KEM, Bourgeois D, Dahan K, Vignard V, Bonneau D, Colin E, Barth M, Camby C, Baujat G, Briceño I, Gómez A, Deb W, Conrad S, Besnard T, Bézieau S, Krüger E, Küry S, Stankiewicz P. Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype. Genetics In Medicine : Official Journal Of The American College Of Medical Genetics 2022, 24: 179-191. PMID: 34906456, DOI: 10.1016/j.gim.2021.09.005.Peer-Reviewed Original Research
2021
Mutations of the histone linker H1–4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4
Tremblay MW, Green MV, Goldstein BM, Aldridge AI, Rosenfeld JA, Streff H, Tan WD, Craigen W, Bekheirnia N, Al Tala S, West AE, Jiang YH. Mutations of the histone linker H1–4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4. Human Molecular Genetics 2021, 31: 1430-1442. PMID: 34788807, PMCID: PMC9271223, DOI: 10.1093/hmg/ddab321.Peer-Reviewed Original ResearchConceptsC-terminusGenome-wide transcriptome analysisRahman syndromeUnderstanding of mutationsHistone H1.4Neuronal genesTranscriptome analysisAbnormal C-terminusFunctional categoriesFunctional characterizationNeuropeptide signalingN-terminusDe novo heterozygous mutationsSupport of pathogenicitySmall insertionsFunctional consequencesNovo heterozygous mutationRat hippocampal neuronsFrameshift mutationMutationsH1.4Rare genetic disorderSevere intellectual disabilityGenesClinical featuresD‐bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia
Werner KM, Cox AJ, Qian E, Jain P, Ji W, Tikhonova I, Castaldi C, Bilguvar K, Knight J, Ferdinandusse S, Fawaz R, Jiang Y, Gallagher PG, Bizzarro M, Gruen JR, Bale A, Zhang H. D‐bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia. American Journal Of Medical Genetics Part A 2021, 188: 357-363. PMID: 34623748, PMCID: PMC8678290, DOI: 10.1002/ajmg.a.62520.Peer-Reviewed Original ResearchConceptsBifunctional protein deficiencyEarly mortalityClinical spectrumPersistent hypoglycemiaDBP deficiencyFat-soluble vitamin deficiencyImportant prognostic informationProtein deficiencyEnzyme deficiencyYears of lifePeroxisomal enzyme deficienciesResidual enzyme functionAbsent enzyme activityRapid whole-genome sequencingUnexplained hypoglycemiaEarly managementPrognostic informationVitamin deficiencyClinical severityNeonatal hypotoniaHigh burdenPeroxisomal dysfunctionPatient's fatherPsychomotor delayLong-chain fatty acidsBAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology
Zhang L, Qian Y, Li J, Zhou X, Xu H, Yan J, Xiang J, Yuan X, Sun B, Sisodia SS, Jiang YH, Cao X, Jing N, Lin A. BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology. IScience 2021, 24: 102942. PMID: 34430820, PMCID: PMC8369003, DOI: 10.1016/j.isci.2021.102942.Peer-Reviewed Original ResearchNeuronal apoptosisAlzheimer's diseaseMicroglial phagocytosisMicroglial NLRP3 inflammasome activationDisease pathologyCommon progressive neurodegenerative diseaseProgressive neurodegenerative diseaseAlzheimer's disease pathologyNLRP3 inflammasome activationPotential therapeutic targetNeuroinflammatory microgliaAD miceAβ clearanceAD pathologyBad pro-apoptotic activityAD patientsInflammasome activationTherapeutic targetMemory deficitsPro-apoptotic proteinsNeuroinflammationNeurodegenerative diseasesSpatial learningInactivation of BadPro-apoptotic activityExome Sequencing Analysis on Products of Conception: A Cohort Study to Evaluate Clinical Utility and Genetic Etiology for Pregnancy Loss
Zhao C, Chai H, Zhou Q, Wen J, Reddy U, Kastury R, Jiang Y, Mak W, Bale A, Zhang H, Li P. Exome Sequencing Analysis on Products of Conception: A Cohort Study to Evaluate Clinical Utility and Genetic Etiology for Pregnancy Loss. Obstetrical & Gynecological Survey 2021, 76: 468-469. DOI: 10.1097/01.ogx.0000791680.43228.b1.Peer-Reviewed Original Research