2022
A 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 results
2017
Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib
Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130: 2307-2316. PMID: 28972011, PMCID: PMC5701526, DOI: 10.1182/blood-2017-08-801191.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChemokinesChildChild, PreschoolClass I Phosphatidylinositol 3-KinasesDemographyDose-Response Relationship, DrugFemaleHumansImmunoglobulin MImmunologic Deficiency SyndromesInfantLymph NodesLymphocyte ActivationMaleMolecular Targeted TherapyMutationOrgan SizePhenotypePrimary Immunodeficiency DiseasesProtein Kinase InhibitorsPyridinesPyrimidinesRatsSpleenT-LymphocytesTOR Serine-Threonine KinasesTransfectionConceptsImmune dysregulationT cellsB cellsElevated serum immunoglobulin MPI3K/Akt pathway activityDose-escalation studyLymph node sizeSenescent T cellsWeeks of treatmentDose-dependent suppressionTransitional B cellsTumor necrosis factorDose-dependent reductionPrecision medicine therapiesSerum immunoglobulin MNaive B cellsT cell blastsAkt pathway activityAPDS patientsPI3Kδ pathwayInflammatory markersPD-1Clinical parametersSpleen volumeImmune deficiencyConformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1
Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 1982-1987. PMID: 28167755, PMCID: PMC5338455, DOI: 10.1073/pnas.1617244114.Peer-Reviewed Original ResearchMeSH KeywordsCatalytic DomainCell MembraneClass I Phosphatidylinositol 3-KinasesClass Ia Phosphatidylinositol 3-KinaseEnzyme AssaysEnzyme InhibitorsGain of Function MutationHumansImmunologic Deficiency SyndromesMass SpectrometryModels, MolecularPhenotypePhosphatidylinositol 3-KinasesPrimary Immunodeficiency DiseasesProtein ConformationPurinesQuinazolinonesRandomized Controlled Trials as TopicSequence DeletionConceptsRegulatory subunitCatalytic subunitClass IA catalytic subunitsHydrogen-deuterium exchange mass spectrometryOncogenic mutationsP85 regulatory subunitExchange mass spectrometryClass IA phosphoinositideP85α regulatory subunitPI3K delta syndromeCSH2 domainMolecular basisP110δ catalytic subunitMolecular mechanismsBiochemical assaysSubunits